Treatment methods for neuroendocrine tumors

Abstract

This invention provides combinations and methods for treating cancers that overexpress somatostatin receptors, such as neuroendocrine tumors (NETs). [Solution] The present invention provides a novel therapy based on a combination of a peptide receptor radionuclide therapy (PRRT) agent and a cancer immunotherapy (IO) agent, wherein the IO agent is selected from the group consisting of LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, TGF-β inhibitors, IL15 / IL-15RA complexes, and selected PD-1 inhibitors.

Description

[Technical Field]

[0001] Sequence List This application concerns the electronically submitted sequence listing in ASCII format (file name PAT058249 This sequence listing, including _SL.txt, is incorporated herein by reference in its entirety.

[0002] This invention relates to cancers that overexpress somatostatin receptors, such as neuroendocrine tumors (NETs). The present invention relates to a method for treating [the condition]. In particular, the present invention relates to peptide receptor radionuclide therapy (PRRT). A novel therapy based on a combination of an agent and an immunotherapy agent for cancer (IO), wherein the IO treatment Therapies include LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, and TGF-β inhibitors. Selected from the group consisting of IL15 / IL-15RA complex and selected PD-1 inhibitors. To provide novel therapies. [Background technology]

[0003] A combination of peptide receptor radionuclide therapy (PRRT) agents and cancer immunotherapy (IO) agents. Methods for treating NET tumors based on the following international publicly available information incorporated herein by reference. In brochure No. 2016 / 207732, Buono and Sierra It is stated as follows.

[0004] Peptide receptor radionuclide therapy (PRRT) is an established tumor immunosuppressive network. It provides enhanced immunogenicity-promoting effects in relation to the correction of [condition].

[0005] Immunotherapy (IO) for cancer neutralizes established cancer resistance and effectively stimulates tumor-specific immune responses. Restore the answer.

[0006] Internal radiation therapy of tumor cells provided by PRRT causes damage to the tumor and tumor cells This leads to the release of the primordial agent, making the tumor more easily detected by the immune system. IO therapy This provides immune checkpoint blockers and thus enhances the immune anti-tumor T cell response. In this configuration, IO therapy synergistically enhances the effects of internal radiation therapy by PRRT. do.

[0007] NET tumors overexpress somatostatin receptors, so drugs such as octreotate are effective against them. PRRT based on matostatin receptor conjugates is an effective target for treating such tumors. This is a chemical approach.

[0008] The radioactive nuclide lutetium-177 (177Lu) undergoes high energy during beta-minus decay. —It has been shown that by releasing electrons, it efficiently damages the DNA of tumor cells and causes tumor cell death. It has been released. Radioactive nuclides are metal chelate units that are covalently bound to the acceptor binder, for example. It binds to the somatostatin receptor binder via the DOTA molecule. It forms a complex with a radionuclide. Examples of somatostatin receptor binders that are linked to the chelate units they form include: It is also available as a Lutathera. 177 Lu-DOTA-TATE or Lutetium (177Lu) is also known as oxodotreotide (INN). 177 Lu-DO TA 0 -Try 3 - It is octreotete. [Overview of the project] [Means for solving the problem]

[0009] International Publication No. 2016 / 207732 is a pamphlet on the combination of PRRT and IO therapy. This document describes the general treatment concepts for combination therapy, particularly focusing on the PD-1 / PD-L1 and CTLA-4 pathways. The present invention provides a combination with an IO inhibitor. Peptide receptor radionuclide therapy (P) for use in treating cancers that overexpress P receptors. Novel combinations comprising an RRT agent and one or two cancer immunotherapy (IO) agents The IO treatment agents include LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, and T From GF-β inhibitors, IL15 / IL-15RA complexes, and improved PD-1 inhibitors Selected from the group, the PD-1 inhibitor is spartalizumab, pembrolizumab, piden Ilizumab, durvalomab, atezolizumab, avelumab, MEDI0680, REG N2810, TSR-042, PF-06801591, BGB-A317, BGB-1 A novel combination selected from the group consisting of 08, INCSHR1210 and AMP-224 We will provide a matching service.

[0010] This invention particularly concerns the PPRT agent lutetium ( 177 Lu) With oxodotreotide and especially This provides a combination for treating NET tumors.

[0011] The combination according to the present invention may include one or two further anticancer agents.

[0012] In the combination according to the present invention, the LAG-3 inhibitors are LAG525 and BMS-98. It can be selected from 6016 or TSR-033.

[0013] In the combination according to the present invention, the TIM-3 inhibitor is MBG453 or TSR-0 It could be 22.

[0014] In the combination according to the present invention, the GITR agonist is GWN323, BMS-9 86156, MK-4166, MK-1248, TRX518, INCAGN1876, You can choose between the AMG 228 or the INBRX-110.

[0015] In the combination according to the present invention, the TGF-β inhibitor is XOMA 089 or Freso It could be limumab.

[0016] In the combination according to the present invention, the IL-15 / IL-15RA complex is NIZ98 5. ATL-803 or CYP0150 may be selected.

[0017] Further anticancer agents according to the present invention include, in particular, octreotide, lanreotide, baproreotide, Pasireotide, satreotide, everolimus, temozolomide, telotoritin, suniti From the group consisting of nib, sulfatinib, ribociclib, entinostat, and pazopanib It can be chosen.

[0018] Neuroendocrine tumors (NETs) that can be treated by the combination according to the present invention include gastrointestinal and pancreatic neuroendocrine tumors. Transendocrine tumors, carcinoid tumors, pheochromocytoma, paraganglioma, medullary thyroid carcinoma, pulmonary neuropathic tumors Secretory tumors, thymic neuroendocrine tumors, carcinoid tumors, or pancreatic neuroendocrine tumors, pituitary adenomas Adrenal tumors, Merkel cell carcinoma, breast cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, head and neck tumors cancer, urothelial carcinoma (bladder), renal cell carcinoma, hepatocellular carcinoma, GIST, neuroblastoma, bile duct tumor, child Cervical tumors, Ewing's sarcoma, osteosarcoma, small cell lung cancer (SCLC), prostate cancer, melanoma, cerebrospinal fluid Scirrhoma, glioma, medulloblastoma, hemangioblastoma, supratentorial tumor, neuroectodermal tumor, and sensory neuroblastoma It is selected from the group consisting of the following.

[0019] Further NET tumors that can be treated by the combination according to the present invention are functional carcinoid tumors, insulinomas, gastrin-producing tumors, vasoactive intestinal peptide (VIP) tumors, glucagon-producing tumors, serotoninomas, histaminomas, ACTH tumors, pheochromocytomas, and somatostatin-producing tumors, and may be selected from the group consisting of

[0020] In the combination according to the present invention, the PRRT agent lutetium ([[]]END]] 177 Lu) oxodotate is (a) a complex, (ai) a radionuclide 177Lu (lutetium-177) which provides radioactivity at a concentration providing a radioactivity of 250 to 500 MBq / mL by volume measurement, and (aii) a somatostatin receptor-binding peptide [DOTA octreotate 0 , D- Phe 1 , Tyr 3 octreotate formed by; (b) a stabilizer against radiolysis, (bi) gentisic acid at a concentration of 0.5 to 1 mg / mL , and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; (c) diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL or a salt thereof; and (d) an acetate buffer, (di) acetic acid at a concentration of 0.3 to 0.7 mg / mL; and (dii) sodium acetate at a concentration of 0.4 to 0.9 mg / mL and preferably provides a pH of 4.5 to 6.0, preferably a pH of 5.0 to 5.5 acetate buffer and can be formulated as an aqueous pharmaceutical solution containing

[0021] This pharmaceutical aqueous solution preferably contains gentisinic acid in the complex form of components (ai) and (aii). It is present in the compound, and ascorbic acid is added after the complex formation of components (ai) and (aii). It can be prepared in a manner that allows it to be prepared.

[0022] The pharmaceutical aqueous solutions formulated and prepared by this method are highly concentrated, resulting in a small injection volume. Furthermore, it has high tolerance due to its moderate pH and the absence of ethanol, and is ready-made This PRRT agent can be provided as a formulation. 72 when stored at room temperature (25°C) It has the advantage of being stable in terms of chemical purity and radiochemical purity (≥95%) up to a certain time.

[0023] The present invention provides the following embodiments.

[0024] 1. For use when treating somatostatin receptor overexpressing cancer in the subject, Plitter receptor radionuclide therapy (PRRT) agents and one or two cancer immunotherapy (IO) agents A combination including the IO treatment agent is a LAG-3 inhibitor and a TIM-3 inhibitor. , GITR agonist, TGF-β inhibitor, IL15 / IL-15RA complex and PD- A group consisting of one inhibitor is selected, and the PD-1 inhibitor is spartalizumab, pembrow Lizumab, Pidilizumab, Durvalomab, Atezolizumab, Avelumab, MEDI0 680, REGN2810, TSR-042, PF-06801591, BGB-A31 Selected from the group consisting of 7, BGB-108, INCSHR1210, and AMP-224. A combination.

[0025] 2. A method for treating somatostatin receptor overexpressing cancer in a subject, comprising a peptide A combination of receptor radionuclide therapy (PRRT) agents and one or two cancer immunotherapy (IO) agents. The IO therapeutic agent includes administering it to a combination of factors, and the IO therapeutic agent is a LAG-3 inhibitor, TIM- 3 inhibitors, GITR agonists, TGF-β inhibitors, IL15 / IL-15RA complex and A selection is made from the group consisting of PD-1 inhibitors, and the PD-1 inhibitor is spartalizumab, Pembrolizumab, pidilizumab, durvalomab, atezolizumab, avelumab, M EDI0680, REGN2810, TSR-042, PF-06801591, BGB - From the group consisting of A317, BGB-108, INCSHR1210 and AMP-224 The method to be chosen.

[0026] 3. PRRT agents contain the radioactive nuclide lutetium-177 ( 177 Lu) and chelating agents A combination for use in Embodiment 1, including a bound somatostatin receptor-binding molecule or This is the method of Embodiment 2.

[0027] 4. Somatostatin receptor binding molecules include octreotide, octreotate, and lanreotide. A set of agents selected from the group consisting of tide, bapleotide, pasireotide, and satreotide. A combination or method for using state 3.

[0028] 5. The chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10 - A combination or method for use of Embodiment 4, wherein the component is tetraacetic acid (DOTA).

[0029] 6. The somatostatin receptor binding molecule linked to the chelating agent is DOTA-OC:[D OTA0,D-Phe1] Octreotide, DOTA-TOC:[DOTA 0 ,D-Ph e1 ,Tyr 3 Octreotide (i.e., edtreotide), DOTA-NOC:[DOT A 0 ,D-Phe 1 ,1-Nal 3 ] Octreotide, DOTA-TATE:[DOTA 0 ,D-Phe 1 ,Tyr 3 Octreotate (i.e., oxodotreotide), DOTA -LAN:[DOTA 0 ,D-β-Nal 1 ]Lanreotide, DOTA-VAP:[DO TA 0 ,D-Phe 1 ,Tyr 3 ] bapreotide, satreotide, trizoxetane and sa A combination for use in Embodiment 3, selected from the group consisting of treotide tetraxetan. Method or technique.

[0030] 7. PRRT agents contain lutetium ( 177 Lu) Oxodotreotide (that is 177 Lu[ DOTA 0 ,D-Phe 1 ,Tyr 3 The use of Embodiment 1 is octreotate. A combination or method of Embodiment 2 for this purpose.

[0031] 8. PRRT agents include, for example, lutetium ( 177 Lu) Is it oxodotreotide? or 177 Lu-Edtreotide is (a) A complex, (ai) The radioactive nuclide is 177Lu (lutetium-177), and it is 250-500 Radioactive nuclide 177Lu(Lu) at concentrations that provide radioactivity by volume measurement in MBq / mL Tethium-177), and (aii) DOTA-linked somatostatin receptor-binding peptides, e.g., oxodot Leotide or edtreotide A complex formed by; (b) Stabilizer against radiolysis, (bi) Gentisic acid at a concentration of 0.5-1 mg / mL , and (bii) ascorbic acid at a concentration of 2.0 to 5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL or its salt; and (d) Acetate buffer, (di) Acetic acid at a concentration of 0.3-0.7 mg / mL; and (dii) Sodium acetate at a concentration of 0.4-0.9 mg / mL It consists of a pH of 4.5 to 6.0, preferably 5.0 to 5.5. The acetate buffer to be provided A combination for use in any one of Embodiments 3 to 7, formulated as a pharmaceutical aqueous solution containing Combination or method.

[0032] 9. Gentisic acid is present during the complex formation of components (ai) and (aii), and asco Rubic acid is added after the complex formation of components (ai) and (aii), as in the use of Embodiment 8. A combination or method for this purpose.

[0033] 10. LAG-3 inhibitors include LAG525, BMS-986016, or TSR-033 A combination or implementation for use of any one of Embodiments 1, 3 to 9, selected from the above. One of the methods from Forms 2 to 9.

[0034] 11. The TIM-3 inhibitor is MBG453 or TSR-022, Embodiments 1, 3 A combination for use of any one of the ~10 or any one of the embodiments 2~10 method.

[0035] 12. GITR Agonists: GWN323, BMS-986156, MK-4166 MK-1248, TRX518, INCAGN1876, AMG 228 or INBR A combination for use of any one of embodiments 1, 3 to 11, selected from X-110. The method described above or any one of the embodiments 2 to 11.

[0036] 13. The TGF-β inhibitor is XOMA 089 or fresolimmab, Embodiment 1 , a combination for use of any one of 3 to 12 or any one of Embodiments 2 to 12 Two methods.

[0037] 14. IL-15 / IL-15RA complex is NIZ985, ATL-803, or CY A combination for use of any one of the embodiments 1, 3 to 13, selected from P0150 The method described above or any one of the embodiments 2 to 13.

[0038] 15. Using any one of Embodiments 1, 3 to 14, comprising one or two further anticancer agents. A combination for use or any one of embodiments 2 to 14.

[0039] 16. Further anticancer drugs include octreotide, lanreotide, baproreotide, and pasireotide. D, satreotide, everolimus, temozolomide, telotoritinib, sunitinib, sal Selected from the group consisting of fatinib, ribociclib, entinostat, and pazopanib. , combinations or methods for the use of Embodiment 15.

[0040] 17. Somatostatin receptor overexpression cancer is a neuroendocrine tumor (NET), in practice A combination of any one of embodiments 1, 3 to 16, or any one of embodiments 2 to 13 for use. Or one method.

[0041] 18. Neuroendocrine tumors (NETs) include gastrointestinal and pancreatic neuroendocrine tumors, carcinoid tumors, and brown tumors. Cell tumor, paraganglioma, medullary thyroid carcinoma, pulmonary neuroendocrine neoplasm, thymic neuroendocrine neoplasm, cartilage Noid tumors or pancreatic neuroendocrine tumors, pituitary adenomas, adrenal tumors, Merkel cell carcinomas, breast cancer, non Hodgkin lymphoma, Hodgkin lymphoma, head and neck tumors, urothelial carcinoma (bladder), renal cell carcinoma, liver Cellular carcinoma, GIST, neuroblastoma, cholangiocarcinoma, cervical tumor, Ewing's sarcoma, osteosarcoma, Small cell lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, tetracytoma Embodiment 1 is selected from the group consisting of primitive neuroblastomas, neuroectodermal tumors, and sensory neuroblastomas. A combination or method for using item 7.

[0042] 19. Neuroendocrine tumors (NETs) include functional carcinoid tumors, insulinomas, and gas tumors. Trin-producing tumors, vasoactive intestinal peptide (VIP) tumors, glucagon-producing tumors, serotonin This consists of nomas, histaminomas, ACTH tumors, pheochromocytomas, and somatostatin-producing tumors. A combination or method for using Embodiment 17, selected from the group.

[0043] The combinations described herein offer advantageous anticancer effects, such as enhanced anticancer effects and reduced toxicity. It can provide reduction and / or reduction of side effects. For example, the first therapeutic agent, for example, as described herein. Any of the indicated therapeutic agents and a second therapeutic agent, for example, one or more additional therapeutic agents or all of them Compared to the dose of monotherapy, what would be required to achieve the same therapeutic effect is It can be administered in small doses. Therefore, using the aforementioned combination therapy, growth including cancer can be treated. Compositions and methods for treating sexual disorders are disclosed.

[0044] In some embodiments, the combinations described herein may affect the subject, for example, the present invention. The methods for treating subjects with cancer as described in the document are to be combined as part of a treatment regimen. The administration of the drug is included in one embodiment. The above includes, for example, combinations of 2, 3, or 4. In some embodiments, the treatment regime The system has at least one phase and optionally two phases, for example, a first phase and a second phase. It is administered to elephants. In some embodiments, Phase 1 includes a dose escalation phase. In this state, Phase 1 consists of one or more dose escalation phases, for example, the first, second, or third dose escalation phase. This includes, in some embodiments, the dose escalation phase as described herein, for example. This includes administration of a combination of two, three, four or more therapeutic agents. Some embodiments In this, Phase 2 includes a dose expansion phase. In some embodiments, the dose expansion phase is, for example If, a combination comprising two, three, four or more therapeutic agents as described herein This includes the administration of the dose. In some embodiments, the dose expansion phase is the same as the dose escalation phase, 2, 3, 4. Includes one or more therapeutic agents.

[0045] In some embodiments, the first dose escalation phase involves two therapeutic agents, for example, as described herein. This includes the administration of a combination of two therapeutic agents, with a maximum of one or both therapeutic agents. The maximum tolerated dose (MTD) or recommended dose for expansion (RDE) is determined. In some embodiments, Prior to the first dose escalation phase, the subject was administered as a monotherapy in the first dose escalation phase. It was administered along with one of the therapeutic agents.

[0046] In some embodiments, the second dose escalation phase involves three therapeutic agents, for example, those described herein. This includes the administration of a combination of three therapeutic agents, relating to one, two, or all of the therapeutic agents. The maximum tolerated dose (MTD) or recommended dose for expansion (RDE) is determined. (Some embodiments) In some implementations, the second dose escalation phase begins after the first dose escalation phase has finished. In this state, the second dose escalation phase involves administering one or more of the therapeutic agents in the first dose escalation phase. This includes the above administration. In some embodiments, the second dose escalation phase is performed in accordance with the first dose escalation phase. It will be implemented without any intervention.

[0047] In some embodiments, the third dose escalation phase involves four therapeutic agents, for example, those described herein. This includes combination administration of four therapeutic agents, with one, two, three or all of the therapeutic agents being used. The maximum tolerated dose (MTD) or recommended dose for expansion (RDE) is determined. In some embodiments, In this case, the third dose escalation phase begins after the first or second dose escalation phase has been completed. In the embodiment, the third dose escalation phase is the administration of the therapeutic agent in the second dose escalation phase. Includes one or more (e.g., all) doses. In some embodiments, the third dose escalation phase is , including administration of one or more therapeutic agents administered in the first dose escalation phase. Some embodiments In this case, the third dose escalation phase is implemented without performing the first, second, or both dose escalation phases. It is done.

[0048] In some embodiments, the dose expansion phase occurs after the completion of the first, second, or third dose escalation phase. It begins later. In some embodiments, the dose expansion phase is a dose escalation phase, for example, the first, second or This includes the administration of a combination of drugs administered in a third dose-escalation phase. In one embodiment, Biopsies are obtained from subjects in the dose expansion phase. In one embodiment, the subject is NE T tumors, such as SCLC, are treated.

[0049] While not bound by theory, in some embodiments, dose escalation and dose expansion phases are used. A treatment regimen that includes a phase may involve the introduction of new drugs or regimens for combination, or combination This enables the rapid generation of combinations and / or the evaluation of the safety and activity of acceptable combinations. It is thought that...

[0050] Additional features or embodiments of the methods, compositions, drug formulations and kits described herein are , including one or more of the following: [Modes for carrying out the invention]

[0051] definition When used herein, the articles “a” and “an” are used with respect to their respective articles. It refers to one or more (for example, at least one) grammatical referents of a word.

[0052] In this specification, the term "or" means "and / " unless otherwise clearly indicated by the context. It is used to mean "or" and is also used synonymously with it.

[0053] "Approximately" and "about" generally refer to quantities measured given the nature or precision of the measurement. This refers to the acceptable degree of error regarding . The exemplary degree of error is given Within 20 percent (%) of the value or range of values, typically within 10 percent and more typically It is within 5%.

[0054] When used herein, the articles “a” and “an” are used with respect to their respective articles. It refers to one or more (for example, at least one) grammatical referents of a word.

[0055] In this specification, the term "or" means "and / " unless otherwise clearly indicated by the context. It is used to mean "or" and is also used synonymously with it.

[0056] "Approximately" and "about" generally refer to quantities measured given the nature or precision of the measurement. This refers to the acceptable degree of error regarding . The exemplary degree of error is given Within 20 percent (%) of the value or range of values, typically within 10 percent and more typically It is within 5%.

[0057] "Combination" or "in combination with ~" means administering the therapies or treatments at the same time. This includes having to and / or having to be formulated for delivery together. Although not intended to be so, such delivery methods are described herein. It is within the range of being able to do so. The therapeutic agent in this combination is one or more other additional therapies or treatments. It can be administered simultaneously with, before, or after the drug. The therapeutic agent or therapy protocol is They can be administered in any order. Generally, each drug is administered according to the prescribed order for that drug. It will be administered according to the dosage and / or time schedule. Furthermore, this combination is beneficial The additional therapeutic agents used may be administered together in a single composition or individually in different compositions. It will be understood that it may be administered. Generally, additional therapeutic agents used in combination. It is expected that it will be used at a level that does not exceed the level of individual use. In the embodiment of the part, the levels used in the combination are greater than the levels used individually. It will also likely decrease.

[0058] In some embodiments, additional therapeutic agents are administered in therapeutic or lesser doses. In terms of morphology, the concentration of the second therapeutic agent required to achieve inhibition, for example, growth inhibition, is When the second therapeutic agent is administered in combination with the first therapeutic agent, for example, an anti-PD-1 antibody molecule, The second therapeutic agent is lower than when administered individually. In certain embodiments, inhibition, for example The concentration of the first therapeutic agent required to achieve growth inhibition is such that the first therapeutic agent is equivalent to the second therapeutic agent. When administered in combination, the risk is lower than when the first therapeutic agent is administered individually. In an embodiment of the combination therapy, it is necessary to achieve inhibition, for example, growth inhibition. The concentration of the second therapeutic agent is lower than the therapeutic dose of the second therapeutic agent as monotherapy, for example 1 0-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70% 70-80% or 80-90% lower. In certain embodiments, combination therapy, The concentration of the first therapeutic agent required to achieve inhibition, for example, growth inhibition, is as a monotherapy. Lower than the therapeutic dose of the first treatment, for example, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower.

[0059] The terms "inhibitor," "inhibitor," or "antagonist" refer to a given molecule, such as an immunosuppressant. This includes a reduction in specific parameters of the cytotoxic inhibitor, such as a decrease in activity. For example, at least 5 %, 10%, 20%, 30%, 40% or more of activity, for example, the activity of a given molecule Inhibition, for example, an inhibitory molecule, is included in this term. Therefore, inhibition does not need to be 100%. stomach.

[0060] "Fusion proteins" and "fusion polypeptides" are covalently linked to each other. Each part consists of two parts, each of which is a polypeptide having different properties. This refers to polypeptides that contain [a specific component]. Their properties include biological characteristics such as in vitro or in vivo activity. These properties can be simple chemical properties such as binding to a target molecule or catalyzing a reaction. It can also be a physical or tactile property. The two parts are connected by a single peptide bond or a peptide bond. They can be directly linked via Drinker, but they are both within the same reading frame.

[0061] The terms "activator," "activator," or "agonist" refer to a given molecule, such as a co-stimulator molecule. This includes increasing specific parameters, such as activity, for example, at least 5%, 10%, 25%. This term includes increases in activity of %, 50%, 75%, or more, such as an increase in co-stimulatory activity. ru.

[0062] The term "anti-cancer effect" refers to, for example, a reduction in tumor volume, a reduction in the number of cancer cells, and a reduction in the number of tumor metastases. Various factors associated with cancer, such as a decrease in average life expectancy, a decrease in cancer cell proliferation, a decrease in cancer cell survival, or a reduction in cancerous status. This includes, but is not limited to, the remission of physiological symptoms, and is manifested by various means. It refers to the biological effect obtained. "Anti-cancer effect" refers to the prevention of cancer development in the first part. This can also be revealed by the capabilities of peptides, polynucleotides, cells, and antibodies.

[0063] The term "antitumor effect" refers to, for example, a reduction in tumor volume, a decrease in the number of tumor cells, and tumor cell proliferation. This includes, but is not limited to, a reduction in tumor cell survival, or a reduction in tumor cell survival, by various means. This refers to the biological effects that can be alleviated.

[0064] The term "cancer" refers to a disease characterized by the rapid and uncontrolled proliferation of abnormal cells. This refers to a disease. Cancer cells can spread locally or to other parts of the body via the bloodstream and lymphatic system. This is possible. Examples of various cancers are described herein, including breast cancer, prostate cancer, ovarian cancer, cervical cancer, Examples include skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, and lung cancer. These are, but are not limited to, the following. The terms "tumor" and "cancer" are synonymous in this specification. They are used in a general sense, and for example, both terms encompass solid and liquid tumors, such as scattered or circulating tumors. Includes. When used herein, the terms “cancer” or “tumor” include precancerous and malignant cancers. and tumors. When used herein, the term "cancer" means primary malignant cells or tumors. For example, the cells have not metastasized to any other part of the body besides the initial malignant tumor or the site of the tumor. (and secondary malignant cells or tumors (for example, in a secondary site different from the site of the initial tumor)) and secondary malignant cells or tumors (for example, in a secondary site different from the site of the initial tumor). This includes those arising from metastasis, which is the transfer of malignant or tumor cells.

[0065] As used herein, the terms “to treat,” “treatment,” and “treating” are 1 Disorders resulting from the administration of one or more therapies, such as the progression and severity of proliferative disorders and / or reduction or improvement of the duration or one or more symptoms of the disorder (preferably one or more) This refers to the improvement of recognizable symptoms. In specific embodiments, the terms "to treat" and "to treat" are used. The terms "placed" and "being treated" do not necessarily mean that the patient will be aware of the tumor's growth, etc. This refers to improvement in at least one measurable physical parameter of proliferative disorders. Other implementations In this context, the terms "to treat," "treatment," and "treating" can be recognized, for example, Physical stabilization due to symptom stabilization, for example, physiological or both stabilization due to physical parameter stabilization This refers to inhibiting the progression of either of the proliferative disorders. In other embodiments, the term "treat" is used. "Treatment" and "being treated" refer to a reduction or stabilization of tumor size or the number of cancerous cells. .

[0066] The compositions and methods of the present invention are substantially identical or similar to the specified sequence. Similar sequences, for example, a given sequence and at least 85%, 90%, 95%, 96%, 97%. This includes polypeptides and nucleic acids having sequences that are identical by %, 98%, 99% or more. In relation to sequences, the term "substantially identical" means that the first and second amino acid sequences share a common structural integrity. i) identical to the second amino acid sequence so that it may have the main and / or common functional activity. ii) Conservative substitution of aligned amino acid residues in the second amino acid sequence In this specification, the term "first amino acid" is used to refer to a first amino acid containing a certain sufficient or minimum number of amino acid residues. It is used. For example, a reference sequence, for example, a sequence provided herein, and at least about 85% 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% This is an amino acid sequence containing a common structural domain that has identity.

[0067] In relation to nucleotide sequences, the term "substantially identical" refers to the first and second nucleotides. The sequences encode polypeptides having common functional activity, or common structural polypeptides. A second nucleic acid to encode a ptidodomain or a common functional polypeptide activity Contains a sufficient or minimum number of nucleotides that are identical to the nucleotides aligned in the sequence. This is used herein to refer to a first nucleic acid sequence. For example, a reference sequence, e.g., this one. The sequences provided in the details and at least approximately 85%, 90%, 91%, 92%, 93%, and 94% , nucleotide sequences having 95%, 96%, 97%, 98%, or 99% identity. .

[0068] The term "functional variant" refers to an amino acid sequence that is substantially identical to a naturally occurring sequence. or are encoded by substantially identical nucleotide sequences and are naturally occurring. This refers to a polypeptide that can possess one or more active sequences.

[0069] Homology or sequence identity between sequences (these terms are used synonymously in this specification) The calculation will be performed as follows:

[0070] To determine the percentage of identity between two amino acid sequences or two nucleic acid sequences, these Align the sequence for optimal comparison purposes (for example, for optimal alignment) A gap can be introduced in one or both of the 1st and 2nd amino acid or nucleic acid sequences, and non Homologous sequences can be ignored for comparison purposes. In a preferred embodiment, ratio The length of the reference arrays aligned for comparison purposes is preferably at least 30% of the length of the reference arrays. Or at least 40%, more preferably at least 50%, 60%, and even more preferably The percentages are at least 70%, 80%, 90%, and 100%. Next, the corresponding amino acids. Compare the amino acid residue or nucleotide at the position or nucleotide position of the first sequence. A certain position in the sequence is the same amino acid residue or nucleo as the corresponding position in the second sequence. If occupied by a cydo, the molecules are identical at that position (as used herein). In this case, the "identity" of an amino acid or nucleic acid is equivalent to the "homology" of an amino acid or nucleic acid. .

[0071] The identity percentage between the two sequences is introduced for optimal alignment of the two sequences. Considering the number of gaps that need to be made and the length of each gap, these arrangements It is a function of the number of shared identical positions.

[0072] The comparison of arrays and the determination of the percentage of identity between two arrays are performed using mathematical algorithms. This can be achieved. In a preferred embodiment, identity between two amino acid sequences - Cent is Blossum62 matrix or PAM250 matrix and 16 , gap weights of 14, 12, 10, 8, 6 or 4 and lengths of 1, 2, 3, 4, 5 or 6 Using one of the weights, the GAP program in the GCG software package (www Needleman and Wunsch (( available at .gcg.com) Determined using the algorithm (1970) J.Mol.Biol.48:444-453) In yet another preferred embodiment, the percentage of identity between two nucleotide sequences The matrix is ​​NWSgapdna.CMP matrix and 40, 50, 60, 70 or 80 Using the gap weights and length weights 1, 2, 3, 4, 5, or 6, the GCG software Determined using the GAP program included in the package (available at www.gcg.com) A particularly preferred set of parameters (and those that should be used unless otherwise specified). ) includes 12 gap penalties, 4 gap extension penalties, and 5 frame shifts. This is a Blossum62 scoring matrix with a gap penalty.

[0073] The percentage of identity between two amino acid or nucleotide sequences is E. Meyers and Using W. Miller's algorithm ((1989) CABIOS, 4:11-17) This algorithm can be determined using the PAM120 weighted residue table and 12 gaps. Using long penalty and 4 gap penalty, the ALIGN program (version 2 It is introduced in version .0.

[0074] The nucleic acid and protein sequences described herein may be used as "query sequences," for example. If other family members or related sequences are identified, then use public databases. A search can be performed. Such a search can be performed by Altschul, et al. (1 990) NBLAST and XBLAST in J.Mol.Biol.215:403-10 This can be done using the program (version 2.0). Nucleotide by BLAST A search was performed using the NBLAST program, with a score of 100 and a word length of 12. A nucleotide sequence homologous to the nucleic acid molecule of the present invention can be obtained using BLAST. We performed a protein search using the XBLAST program, with a score of 50 and a word length of 3. By applying this method, an amino acid sequence homologous to the protein molecule of the present invention can be obtained. For comparative purposes. To obtain a gapped alignment, see Altschul et al., (1997) As described in Nucleic Acids Res. 25:3389-3402, A BLAST with a gap can be used. BLAST and BLAST with a gap When using a program, the default parameters of each program (for example, XBLAS) T and NBLAST can be used. www.ncbi.nlm.nih.go Please refer to v.

[0075] When used herein, the terms "low stringency, medium stringency" Under high stringency or very high stringency conditions, hybrids "To do" describes the conditions related to hybridization and cleaning. The instructions for performing the reaction are referenced in Current Pro. tocols in Molecular Biology,John Wiley&S This can be found in ons, NY (1989), 6.3.1-6.3.6. Aqueous and Non-aqueous methods are described in the references and may be used. The specific hybridization conditions mentioned are as follows: 1) 6°C at approximately 45°C × Low stringency in sodium chloride / sodium citrate (SSC) Under the bridization conditions, followed by 0.2 × SSC and 0.1% SDS, at least Also, wash twice at 50°C (washing temperature is up to 55°C for low stringency conditions). 1) Can be raised; 2) Moderate stringency high in 6×SSC at approximately 45℃ Bridization conditions followed by 1 in 0.2×SSC and 0.1%SDS at 60°C Washing multiple times; 3) High stringency hybrids in 6×SSC at approximately 45°C Isolation conditions followed by at least one cycle at 65°C in 0.2×SSC and 0.1%SDS. Washing; and preferably 4) Hybridization strips of very high stringency The test was conducted using 0.5M sodium phosphate at 65°C, 7% SDS, followed by 0.2×SSC This involves one or more washes at 65°C in 1% SDS. It exhibits very high stringency. Condition (4) is the preferred condition and should be used unless otherwise specified.

[0076] The molecules of the present invention have additional conservation or non-essential properties that do not substantially affect their functions. It is understood that it may have amino acid substitutions.

[0077] The term "amino acid" refers to both naturally occurring and synthetic amino acids, encompassing both amino and acidic functionalities. It includes both sexes and all molecules that can be found in naturally occurring amino acid polymers. This is intended to be the case. Exemplary amino acids are naturally occurring amino acids; their analogues and derivatives. and related substances; amino acid analogs having heteromorphic side chains; and all of the aforementioned stereotypes Includes D- or L-optical isomers. As used herein, the term "amino acid" refers to D- or L-optical isomers. It includes both and peptide mimetic compounds.

[0078] "Conservative amino acid substitution" is when an amino acid residue is replaced with an amino acid residue that has a similar side chain. This is a possible substitution. Families of amino acid residues with similar side chains have been established in the art. These families include amino acids with basic side chains (e.g., ri (Din, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid) (glutamic acid), amino acids having non-charged side chains (e.g., glycine, asparagine) (Glutamine, serine, threonine, tyrosine, cysteine), amino acids with nonpolar side chains ano acids (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine) (e.g., methionine, tryptophan), amino acids with β-branched side chains (e.g., threonine) (Valine, isoleucine) and amino acids having aromatic side chains (e.g., tyrosine, phenylamine) Examples include rualanine, tryptophan, and histidine.

[0079] The terms "polypeptide," "peptide," and "protein" (in the case of a single-stranded protein) are defined in this specification. Used synonymously in writing, it refers to a polymer of amino acids of any length. Polymers are linear or It can be a branched chain, and it may contain modified amino acids, and it may also contain non-amino acids. This can be interrupted. This term refers to modified (e.g., disulfide bond formation, glycosyl) Any other process such as ionization, lipidization, acetylation, phosphorylation, or conjugation with a labeled component. This also includes amino acid polymers (manipulation). Polypeptides can be isolated from natural sources. Alternatively, they can be produced from a eukaryotic or prokaryotic host by recombinant technology, or they are products of the synthesis process. It is possible.

[0080] The terms "nucleic acid," "nucleic acid sequence," "nucleotide sequence," or "polynucleotide sequence" and The terms "polynucleotide" and "deoxyribonucleotide" are used synonymously. Alternatively, polynucleotides of any length, either ribonucleotides or their analogues. This refers to the M-form. Polynucleotides can be single-stranded or double-stranded, and single-stranded... In some cases, it may be a coding strand or a non-coding (antisense) strand. Polynucleotides are, It may contain modified nucleotides such as methylated nucleotides and nucleotide analogs. The sequence of a rheotide can be interrupted by non-nucleotide components. Polynucleotides are labeled Nucleic acids can be further modified after polymerization, such as by conjugation with identifying components. Replacement polynucleotides or genomes, cDNA, semi-synthetic or naturally occurring or non- Either a naturally occurring polynucleotide linked to another polynucleotide or a synthetically derived polynucleotide It could be a renucleotide.

[0081] The term "isolated" as used herein means its original or conventional environment (e.g., This refers to materials extracted from the natural environment (if they exist naturally). For example, Naturally occurring polynucleotides or polypeptides found in living animals are isolated. Although not yet done, some or all of the materials that coexist in nature have been separated by human intervention. The same polynucleotide or polypeptide has been isolated. It may be part of a vector and / or such polynucleotide or poly Peptides may also be part of a composition, and such vectors or compositions may exist in nature. It remains isolated in that it is not part of the environment in which it can be observed.

[0082] Various aspects of the present invention will be described in further detail below. Further definitions throughout this specification may be used. It will be shown.

[0083] antibody molecule In one embodiment, the combination described herein includes a therapeutic agent which is an antibody molecule. nothing.

[0084] As used herein, the term “antibody molecule” means at least one immunoglobulin molecule This refers to proteins containing variant domain sequences. The term antibody molecule is used, for example, to describe full-length, mature proteins. It includes antibodies and antigen-binding fragments of antibodies. For example, an antibody molecule has a heavy (H) chain variable domain sequence. (Abbreviated as VH in this specification) and the light (L) chain variable domain sequence (Abbreviated as VL in this specification) (Omitted) and may include. In another example, an antibody molecule may have two heavy (H) chain variable domains. It includes a sequence and two light (L) chain variable domain sequences, thereby creating two antigen-binding sites. For example, Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single-chain antibodies (example) For example, scFv), single variable domain antibody, diabody (Dab) (bivalent and bivalent). They form heterozygous and chimeric (e.g., humanized) antibodies, and these are formed by the modification of the entire antibody. It can be produced by this method, or it may be de novo synthesized using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. The antibodies and antibody fragments are, but are not limited to, IgG, IgA, IgM, IgD and Any antibody class and any subclass of antibody, including IgE (e.g., IgG1, IgE). The antibodies of the present invention may be monoclonal or poly(IgG2, IgG3, and IgG4). It may be clonal. The antibody is a human antibody, humanized antibody, CDR-transplanted antibody or in vitro. It could also be an antibody produced by [unclear]. The antibody could be, for example, IgG1, IgG2, IgG3, or I It may have a heavy chain constant region selected from gG4. The antibody may be derived from, for example, kappa or lambda. It may also have a selectable light chain.

[0085] Examples of antigen-binding fragments include (i) a monovalent fragment consisting of VL, VH, CL, and CH1 domains. (ii) Two fragments of the Fab fragment; (ii) Two fragments connected by disulfide bridges in the hinge region F(ab')2 fragment, a divalent fragment containing the Fab fragment; (iii) VH and CH1 domer Fd fragment consisting of ; (iv) Fv consisting of the VL and VH domains of a single arm of an antibody fragment, (v) diabody (dAb) fragment consisting of the VH domain; (vi) camelid or camelid variable domain; (vii) single-chain Fv (scFv), e.g. Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5 879-5883); (viii) single domain antibodies are included. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened in the same way as intact antibodies with respect to usefulness.

[0086] The term "antibody" includes intact molecules and functional fragments thereof. The constant region of an antibody can be altered, e.g. mutated, such that the properties of the antibody are modified (e.g., one or more of Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function or complement function is increased or decreased).

[0087] An antibody molecule can also be a single domain antibody. Single domain antibodies can include antibodies in which the complementarity determining region is part of a single domain polypeptide. Examples include heavy chain antibodies, antibodies that are naturally lacking a light chain, single domain antibodies derived from normal four-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies, but are not limited thereto. Single domain antibodies can be any single domain antibody in the art or any future single domain antibody. Single domain antibodies can be from mice, humans, camels, llamas, fish, sharks, goats, It may be derived from any species including, but not limited to, rabbits and cows. Another aspect of the present invention According to, the single domain antibody is a naturally occurring single domain antibody known as a heavy chain antibody lacking a light chain. Such single domain antibodies are disclosed, for example, in WO 94 / 046 78. For clarity, this variable domain derived from a naturally light chain-lacking heavy chain antibody is herein distinguished from the normal VH of a four-chain immunoglobulin and is known as VHH or nanobody. Such VHH molecules are derived from antibodies that occur in camelid species such as camels, llamas, dromedaries, alpacas and guanacos. Other species than camelids may produce light chain-lacking heavy chain antibodies; such VHHs are within the scope of the present invention. The VH and VL regions can be further divided into hypervariable regions called "complementary determining regions" (CDRs) interspersed with more conserved regions called "framework regions" (FR or FW). The ranges of the framework regions and CDRs are precisely defined in several ways

[0088] (Kabat, E.A., et al. (1991) Sequences of Pro teins of Immunological Interest, Fifth Ed ition, U.S. Department of Health and Human

[0089] Services, NIH Publication No. 91-3242; Cho (thia, C. et al. (1987) J. Mol. Biol. 196:901-91 7; and by the AbM antibody modeling software of Oxford Molecular Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and by the AbM antibody modeling software of Oxford Molecular Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and by the AbM antibody modeling software of Oxford Molecular Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and by the AbM antibody modeling software of Oxford Molecular Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and by the AbM antibody modeling software of Oxford Molecular Please refer to the AbM definition used. In general terms, for example, Protein Sequ ence and Structure Analysis of Antibody Variable Domains.In:Antibody Engineering Lab Manual(Ed.:Duebel, S. and Kontermann, See R., Springer-Verlag, Heidelberg.

[0090] The terms "complementarity-determining region" and "CDR" are used herein to mean antigen specificity and This refers to the amino acid sequence within the antibody variable region that confers binding affinity. Generally, each heavy chain variable There are three CDRs in the region (HCDR1, HCDR2, HCDR3) and three in each light chain variable region. There are CDRs (LCDR1, LCDR2, LCDR3).

[0091] The precise amino acid sequence boundaries of a given CDR are as follows: Kabat et al. (1991) “Sequences of Proteins of Immunological Interest,”5th Ed.Public Health Service,N ational Institutes of Health,Bethesda,MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) ) Listed by JMB 273,927-948 ("Chothia" numbering scheme) This can be determined using one of several well-known schemes, including those mentioned above. When used in a specification, a CDR defined by the "Chothia" number scheme is It is sometimes referred to as a "super variable loop."

[0092] For example, according to Kabat, the CDR amino acid residues of the heavy chain variable domain (VH) are numbered 31 - 35 (HCDR1), 50 - 65 (HCDR2), and 95 - 102 (HCDR3); and the CDR amino acid residues of the light chain variable domain (VL) are numbered 24 - 34 (LC DR1), 50 - 56 (LCDR2), and 89 - 97 (LCDR3). According to Ch othia, the CDR amino acids of VH are numbered 26 - 32 (HCDR1), 52 - 5 6 (HCDR2), and 95 - 102 (HCDR3); and the amino acid residues of VL are numbered 26 - 32 (LCDR1), 50 - 52 (LCDR2), and 91 - 96 (LCDR3 ). By combining the CDR definitions of both Kabat and Chothia, the CDRs consist of the amino acid residues 26 - 35 (HCDR1), 50 - 65 (H CDR2), and 95 - 102 (HCDR3) of human VH, and the amino acid residues 24 - 34 ( LCDR1), 50 - 56 (LCDR2), and 89 - 97 (LCDR3) of human VL.

[0093] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence that can form the structure of an immunoglobulin variable domain. For example, this sequence can include all or part of the amino acid sequence of a naturally occurring variable domain. For example, this sequence may or may not include one , two or more N - terminal or C - terminal amino acids, or may include other changes compatible with the formation of the protein structure.

[0094] The term "antigen - binding site" refers to the part of an antibody molecule that contains determinants forming the junction fragment that binds to the PD - 1 polypeptide or its epitope. A protein (or protein mimic)​​​ Regarding this, the antigen-binding site typically forms a junction that binds to the PD-1 polypeptide. It contains one or more loops (at least four amino acids or amino acid mimetic compounds). In terms of type, the antigen-binding site of the antibody molecule has at least one or two CDRs and / or or a highly variable loop or more typically at least 3, 4, 5 or 6 CDRs and / Alternatively, it may include a highly variable loop.

[0095] The terms "monoclonal antibody" or "monoclonal antibody composition" are used herein. When used, it refers to a formulation of an antibody molecule with a single molecular composition. Monoclonal antibody compositions are specific It exhibits single binding specificity and affinity to an epitope. Monoclonal antibodies are hive Methods using redoma technology or methods that do not use hybridoma technology (e.g., recombinant methods) It can be manufactured by ).

[0096] "Effective human" proteins are involved in antibody reactions, such as human anti-mouse antibody (HAMA) reactions. It is a protein that does not induce neutralization. HAMA is used, for example, in the treatment of chronic or recurrent disease conditions. In medical treatment, for example, repeated administration of antibody molecules can pose problems in many situations. HAM Reaction A is due to increased antibody clearance from serum (e.g., Saleh et al.) l.,Cancer Immunol.Immunother.,32:180-190 (See 1990) and also for potential allergic reactions (e.g., Lo Buglio et al., Hybridoma, 5:5117-5123 (1986 (See reference below), which may potentially render repeated antibody administration ineffective.

[0097] The antibody molecule may be a polyclonal or monoclonal antibody. In other embodiments, The antibodies are recombinantly produced, for example, by phage display or combinatorial methods. It can be manufactured.

[0098] Phage display and combinatorial methods for antibody production are relevant to this technology. (For example, Ladner, whose content is incorporated herein by reference) U.S. Patent No. 5,223,409 of Kang et al.; International Patent No. 5,223,409 of Kang et al. Publication No. 92 / 18619; International Publication No. 91 / by Dower et al. Pamphlet No. 17271; International Publication No. 92 / 20791 by Winter et al. Pamphlet No. 92 / 15679 by Markland et al. Fret; Breitling et al. International Publication No. 93 / 01288 pamphlet McCafferty et al.'s International Publication No. 92 / 01047 pamphlet T; Garrard et al.'s International Publication No. 92 / 09690; La dner et al. International Publication No. 90 / 02809 pamphlet; Fuchs e t al.(1991)Bio / Technology 9:1370-1372;Ha y et al. (1992) Hum Antibod Hybridomas 3:8 1-85;Huse et al.(1989)Science 246:1275-1 281;Griffths et al.(1993)EMBO J 12:725-7 34; Hawkins et al. (1992) J Mol Biol 226:88 9-896;Clackson et al.(1991)Nature 352:62 4-628; Gram et al. (1992) PNAS 89:3576-3580 ; Garrad et al. (1991) Bio / Technology 9:137 3-1377;Hoogenboom et al.(1991)Nuc Acid R es 19:4133-4137; and Barbas et al. (1991) PNA (As described in S 88:7978-7982).

[0099] In one embodiment, the antibody is a fully human antibody (for example, an antibody derived from a human immunoglobulin sequence). Antibodies produced in mice genetically engineered to produce bodies, or non-human antibodies, For example, antibodies from rodents (mice or rats), goats, primates (e.g., monkeys), and camels. Yes. Preferably, the non-human antibody is a rodent antibody (mouse or rat antibody). Methods for creating bodies are known in this field.

[0100] Human monoclonal antibodies possess human immunoglobulin genes instead of mouse-derived ones. These can be produced using transgenic mice. These mice are immunized with the target antigen. Using splenocytes from lancegenic mice, regarding human protein epitopes... To create hybridomas that secrete human mAbs with specific affinity (e.g., Wo Brochure for International Application Publication No. 91 / 00906 by od et al., Kuche Rlapati et al. PCT Public International Publication No. 91 / 10741 pamphlet; Brochure for International Application Publication No. 92 / 03918 by Lonberg et al.; Brochure for International Application Publication No. 92 / 03917 by Kay et al.; Lonb erg,N.et al.1994 Nature 368:856-859;Gree n,LLet al.1994 Nature Genet.7:13-21;Mo rrison,SLet al.1994 Proc.Natl.Acad.Sci .USA 81:6851-6855;Bruggeman et al.1993 Y ear Immunol 7:33-40;Tuaillon et al.1993 PNAS 90:3720-3724;Bruggeman et al.1991E See ur J Immunol 21:1323-1326.

[0101] Antibodies have a variable region or portion thereof, such as the CDR, which is found in non-human organisms, such as rats or mice. These may be produced in the present invention. Chimeras, CDR transplants, and humanized antibodies are included in the present invention. It is produced in non-human organisms, such as rats or mice, and then subsequently in humans, for example. Antibodies modified in a variable framework or constant region to reduce antigenicity are, in this case It is included in the definition.

[0102] Chimeric antibodies can be produced by recombinant DNA technology known in this field. Robinson et al. International Patent Publication PCT / U.S. Patent No. 86 / 02269 Specification; Specification of European Patent Application Publication No. 184, 187 of Akira, et al.; Ta Specification of European Patent Application Publication No. 171,496 by Niguchi, M.; Morrison European Patent Application Publication No. 173,494 by et al.; Neuberger e t al.'s International Application Publication No. 86 / 01533 Brochure; Cabilly e U.S. Patent No. 4,816,567 by t al.; Cabilly et al. European Patent Application Publication No. 125,023; Better et al. (1988) Science 240:1041-1043);Liu et al.(1987)P NAS 84:3439-3443;Liu et al.,1987,J.Immun ol.139:3521-3526;Sun et al.(1987)PNAS 84 :214-218;Nishimura et al.,1987,Canc.Res. 47:999-1005;Wood et al.(1985)Nature 314: 446-449; and Shaw et al., 1988, J. Natl Cancer (See Inst.80:1553-1559)

[0103] Humanized or CDR graft antibodies are present in at least one or two, but generally three, all of them. Recipient CDR (heavy and / or light immunoglobulin chains) are affected by donor CDR The antibody will have a replacement. It can be replaced, or only a portion of the CDR can be replaced by a non-human CDR. It is sufficient to simply replace the number of CDRs required for the humanized antibody to bind to PD-1. In other words, the donor becomes a rodent antibody, for example, a rat or mouse antibody, and the recipient becomes It will likely become a human framework or human consensus framework. Typically, The immunoglobulin that provides the CDR is called the "donor," and the immunoglobulin that provides the framework is called the "donor." The globulin is called the "acceptor." In one embodiment, donor immunoglobulin It is non-human (e.g., rodents). The acceptor framework is naturally occurring. (For example, a human) framework or consensus framework or something similar. The sequences are identical for % or more, preferably 90%, 95%, or 99% or more.

[0104] As used herein, the term “consensus sequence” refers to a family of related sequences. This refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) in the sequence. For example, Winnaker, From Genes to Clones (Verlag See sgesellschaft, Weinheim, Germany 1987. (I want to). In a family of proteins, each position in the consensus sequence is a family It is occupied by the amino acid that most frequently appears at that position. Two amino acids If they appear with similar frequency, either one may be included in the consensus sequence. The term "framework" refers to the framework region within a consensus immunoglobulin sequence.

[0105] Antibodies can be humanized by methods known in the art (e.g., all of the contents Morrison, SL, 1985, Scien ce 229:1202-1207, Oi et al. 1986, BioTec Hniques 4:214 and U.S. Patent No. 5,585 by Queen et al. , U.S. Patent No. 089, U.S. Patent No. 5,693,761 and U.S. Patent No. 5,693, (See Specification No. 762.)

[0106] Humanized or CDR-transplanted antibodies can be produced by CDR transplantation or CDR substitution, where One, two, or all of the immunoglobulin chains of CDRs may be replaced. For example, all U.S. Patent No. 5,225,539, the contents of which are expressly incorporated herein by reference. ;Jones et al.1986 Nature 321:552-525;Ver hoeyan et al.1988 Science 239:1534;Beidl er et al.1988 J.Immunol.141:4053-4060;Wi See Winter's U.S. Patent No. 5,225,539. A CDR implantation method that can be used to produce the humanized antibody of the invention is described (March 1987). The specification of the United Kingdom patent application publication No. 2188638A, filed on the 26th; Winter's United States (Japanese Patent No. 5,225,539), the contents of which are expressly incorporated by reference.

[0107] Humanized antibodies in which specific amino acids are substituted, deleted, or added are also within the scope of the present invention. The criteria for selecting amino acids are based on the U.S. Special Measures incorporated herein by reference. The color of U.S. Patent No. 5,585,089, for example, U.S. Patent No. 5,585,089 Columns 12-16, for example, in U.S. Patent No. 5,585,089 It is described as follows. Other technologies related to humanized antibodies were published on December 23, 1992. As described in European Patent Application Publication No. 519596A1 by Adlan et al. It will be done.

[0108] Antibody molecules can be single-chain antibodies. Single-chain antibodies (scFv) can be manipulated (for example) Colcher, D. et al. (1999) Ann NY Acad Sci. 880:263-80; and Reiter, Y. (1996) Clin Cancer See Res 2:245-52). Single-chain antibodies are dimerized or multimerized. Therefore, polyvalent antibodies with specificity for different epitopes of the same target protein are produced. obtain.

[0109] In yet another embodiment, the antibody molecules may be, for example, IgG1, IgG2, IgG3, I Selected from the heavy chain constant regions of gG4, IgM, IgA1, IgA2, IgD, and IgE. In particular, the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4. It has a heavy chain constant region selected from the region. In another embodiment, the antibody molecule is, for example, Having a light chain constant region selected from the kappa or lambda (e.g., human) light chain constant region The constant region may be modified, for example, by mutation, to alter the properties of the antibody (e.g., Fc receptor). Body binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, and / or complement (Increasing or decreasing one or more functions). In one embodiment, the antibody has an effector function. It has and can immobilize complement. In another embodiment, the antibody is an effector - Does not recruit cells or fix complement. In another embodiment, the antibody is an Fc receptor Its ability to bind to the body is reduced or absent. For example, it is Fc-receptor isotypes, subtypes, fragments, or other variants that do not promote binding to the substance. For example, it has a mutagenic or deleted Fc receptor binding region.

[0110] Methods for modifying the constant region of an antibody are known in the art. For example, affinity for effector ligands such as FcR on cells or the C1 component of complement. The modified antibody has at least one amino acid residue in the constant portion of the antibody that is different. It can be produced by replacing with the base (for example, all content is referenced herein). European Patent Application Publication No. 388,151A1, U.S. Patent Application Publication No. 5,624,8 See U.S. Patent No. 21 and U.S. Patent No. 5,648,260. Similar Thai Modifications to the formula may be described, and this applies when applied to mouse or other species immunoglobulins. These features will be reduced or removed.

[0111] Antibody molecules are derivatized into other functional molecules (e.g., other peptides or proteins). It can be obtained or linked. When used herein, a “derivativeized” antibody molecule is It is modified. Derivatization methods include the fluorescent moiety, radioactive nucleotides, This includes, but is not limited to, the addition of affinity ligands such as toxins, enzymes, or biotin. No. Therefore, the antibody molecule of the present invention is a derivative of the immunoadhesion molecule described herein. It is intended to include antibodies in modified and otherwise modified forms. For example, antibody molecules This involves another antibody (e.g., a bispecific antibody or diabody), a detectable drug, and cytotoxicity. Sexual drugs, pharmaceuticals and / or other molecules (streptavidin core area or polyhistidine) Antibodies containing (such as ) or proteins or peptides capable of mediating the association of antibody portions. such as chemical coupling, genetic fusion, and non-covalent bonding between one or more other molecular entities. They can be functionally connected (by combination or other means).

[0112] One type of derivatized antibody molecule is (the same type or, for example, a bispecific antibody). It is produced by crosslinking two or more antibodies (of different types to be generated). As a crosslinking agent, a suitable spacer (e.g., m-maleimidobenzoyl-N-hydroxy A heterodimeric molecule having two distinct reactive groups separated by succinimide ester. Examples include those that are functional or homobifunctional (e.g., disuccinimidyl suberate). Such linkers are manufactured by Pierce Chemical Company, Roc. It is available from Kford, Ill.

[0113] Antibody molecules are typically labeled or used to identify other molecular entities, or for therapeutic purposes (e.g., cytotoxic or inhibitory on cell proliferation). (Sexual) Can be conjugated into drugs or parts. Radioactive isotopes may be used in diagnostic or therapeutic applications. It can be used as follows: Radioisotopes that can bind to anti-PSMA antibodies include α-, β-, or Examples include, but are not limited to, gamma-emitting bodies or beta- and gamma-emitting bodies. Such radiation As for sex isotopes, iodine ( 131 I or 125 I), Yttrium ( 90 Y), Lutechi Hmm ( 177 Lu), Actinium ( 225 Ac), praseodymium, astatine ( 211 At), Rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi), Indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), Rhodium ( 188 Rh ), sulfur (35S), carbon ( 14 C), tritium ( 3 H), chromium ( 51Cr), chlorine ( 36 Cl), cobalt ( 57 Co or 58 Co), iron ( 59 Fe), selenium ( 75 Se ) or gallium ( 67 Examples include, but are not limited to, Ga. Useful as a therapeutic agent. As for radioactive isotopes, yttrium ( 90 Y), Lutetium ( 177 Lu), Acti nium ( 225 Ac), praseodymium, astatine ( 211 At), Rhenium ( 186 R e), bismuth ( 212 Bi or 213 Bi) and rhodium ( 188 Rh) is one example. For example, a useful radioactive isotope for use as a label in diagnosis is iodine ( 1 31 I or 125 I), Indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), carbon ( 14 C) and tritium ( 3 H) or the therapeutic isotopes listed above One or more can be listed.

[0114] The present invention provides radiolabeled antibody molecules and methods for labeling them. In one embodiment, the antibody molecule A method for labeling a molecule is disclosed. The method involves contacting an antibody molecule with a chelating agent, This includes producing conjugated antibodies using radioisotopes. For example, by radioactively labeling with 111 indium, 90 yttrium, and 177 lutetium, This process is used to produce labeled antibody molecules.

[0115] As described above, antibody molecules can be conjugated into therapeutic agents. Therapeutably active radioactive Isotopes have already been described. Examples of other therapeutic agents include Taxol and Cytochalasin. B, Gramicidin D, Ethidium bromide, Emetine, Mitomycin, Etoposide, Tenop Sid, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin Dihydroxyanthracene, mitoxantrone, mitramycin, actinomycete Syn-D, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine Lidocaine, propranolol, puromycin, mytansinoids, for example, mita Cincinol (see U.S. Patent No. 5,208,020), CC-1065 (U.S. Patent No. 5,475,092, U.S. Patent No. 5,585,499, U.S. Patent No. 5, (See Specification Nos. 846, 545) and their analogues or homologues are examples. Examples of drugs include antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thio). Guanine, cytarabine, 5-fluorouracil decarbazine), alkylating agent (for example, Mechloretamine, thioepa chlorambucil ), CC-1065, melphalan, carmustine (BSNU) and lomustine (CCN U), cyclothosphamide, busulfan, dibu Romomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamycin Platinum(II)(DDP) cisplatin, anthracyclines (for example, daunolubicin) (formerly daunomycin and doxorubicin), antibiotics (e.g., dactynomycin) N (formerly actinomycin), bleomycin, mitramycin, and anthramycin (AMC)) and mitotic inhibitors (e.g., vincristine, vinblastine, taxo) Examples include, but are not limited to, uric acid and mytansinoids.

[0116] multispecific antibody molecule In one embodiment, the antibody molecule is a multispecific antibody molecule, for example, it is a multi-specific antibody molecule. It contains a number of immunoglobulin variable domain sequences, and the first of these is immunoglobulin variable The variant domain sequence has binding specificity to the first epitope, and of its multiple components, the second The immunoglobulin variable domain sequence has binding specificity to the second epitope. In one embodiment, the first and second epitopes are the same antigen, for example, the same protein. (or on a subunit of a multimeric protein). In one embodiment, the first and The two epitopes overlap. In one embodiment, the first and second epitopes overlap They do not overlap. In one embodiment, the first and second epitopes are different antigens, for example, different It is located on a protein (or a different subunit of a multimeric protein). In one embodiment In this context, the multispecific antibody molecule has a third, fourth, or fifth immunoglobulin variable domain. Includes. In one embodiment, the multispecific antibody molecule is a bispecific antibody molecule, a triplicate antibody molecule. It is an antibody molecule or a quadruple-specification antibody molecule.

[0117] In one embodiment, the galectin inhibitor is a multispecific antibody molecule. In this context, a multispecific antibody molecule is a bispecific antibody molecule. A bispecific antibody is a 2 It has specificity for the following antigens. The bispecific antibody molecule has specificity for the first epitope. A first immunoglobulin variable domain sequence and a second epitope with binding specificity are used. Characterized by a second immunoglobulin variable domain sequence with binding specificity. In one embodiment, the first and second epitopes are the same antigen, for example, the same protein. It is located on the quality (or subunit of a multimeric protein). In one embodiment, the first and The second epitope overlaps. In one embodiment, the first and second epitopes are They do not overlap. In one embodiment, the first and second epitopes are different antigens, for example It is located on different proteins (or different subunits of a multimeric protein). In this state, the bispecific antibody molecule has a heavy chain that has binding specificity to the first epitope. Binding specificity to the variable domain sequence, the light chain variable domain sequence, and the second epitope. It includes a heavy chain variable domain sequence and a light chain variable domain sequence having a heavy chain variable domain sequence. In one embodiment, A bispecific antibody molecule has a semi-antibody with binding specificity to a first epitope and a second epitope. It contains a semi-antibody having binding specificity to the epitope. In one embodiment, it has dual specific The isoantibody molecule is a semiantibody or fragment thereof that has binding specificity to the first epitope. and a semi-antibody or fragment thereof having binding specificity to a second epitope. Morphologically, a bispecific antibody molecule has binding specificity to the first epitope. cFv or its fragments and scFv having binding specificity to the second epitope or It includes the fragment. In one embodiment, the galectin inhibitor is a bispecific antibody molecule. In one embodiment, the first epitope is located on galectin-1, and the second epitope The pitope is located on galectin-3.

[0118] Protocols for producing bispecific or heterodimer antibody molecules are available in this art. It is known that; for example, the "nobuin" described in U.S. Patent No. 5731168. Hall's Law; for example, International Publication No. 09 / 089004, International Publication No. 06 / As described in pamphlet No. 106905 and international publication pamphlet No. 2010 / 129304. Formation of electrostatic steering Fc pairs as described; for example, International Publication No. 07 / 110205 Strand exchange domain (SEED) heterodimer formation as described in the pamphlet. For example, International Publication No. 08 / 119353, International Publication No. 2011 / 131 As described in Pamphlet No. 746 and International Publication No. 2013 / 060867 Fab arm replacement as described; for example, as described in U.S. Patent No. 4433059 For example, heterodifunctional reagents having amine-reactive groups and sulfhydryl-reactive groups. A double antibody conjugate created by antibody crosslinking using a bispecific structure; for example, As described in U.S. Patent No. 4,444,878, the disulfide between the two heavy chains Through the reduction and oxidation cycles of binding, half-antibodies (heavy-light chain pairs or Fab) are produced from different antibodies. Bispecific antibody determinants produced by combining; for example, U.S. 527 Trifunctional antibodies as described in Specification No. 3743, for example, sulfhydryl(sulf Three Fab' fragments crosslinked via an HCl-reactive group; for example, U.S. Patent No. 55 Biosynthetic binding proteins as described in Specification No. 34254, for example via the C-terminal chain Preferably, the scFv is crosslinked via disulfide or amine-reactive chemical crosslinking. A pair of; for example, a bifunctional antibody as described in U.S. Patent No. 5,582,996. For example, leucine zippers with replaced constant domains (e.g., c-fos and c-ju) Fab fragments having different binding specificities dimerized via n); for example, in the United States As described in Specification No. 5591828, bispecificity and oligospecificity monovalent and Ligo-valent receptors, for example, the CH1 region of one antibody and the V region of the other antibody, which is usually associated with the light chain. Two antibodies linked between the H region via polypeptide spacers (two Fab fragments) The VH-CH1 region of (one side); for example, as described in U.S. Patent No. 5635602. A bispecific DNA antibody conjugate, for example, an antibody mediated by a DNA double-strand fragment. This is the crosslinking of Fab fragments; for example, as described in U.S. Patent No. 5,637,481. Bispecific fusion proteins, for example, two proteins having a hydrophilic helical peptide linker in between An expression construct containing the scFv and the complete constant region; for example, U.S. Patent No. 58 Polyvalent and multispecific binding proteins as described in Specification No. 37242, for example, The first domain and I have a binding region for the Ig heavy chain variable region, generally called a diabody. A polypeptide dimer having a second domain with a binding region for the light chain variable region (double Higher-order structures that generate specific, triplicate, or quadruplicate molecules are also disclosed; for example, As described in the specification of Japanese Patent No. 5837821, dimerized and bispecific / multi A peptide spacer capable of forming valence molecules further binds to the antibody hinge region and CH3 region. Minibody constructs having combined, linked VL and VH chains; forming dimers. This allows for the formation of a bispecific diabody, with short peptide linkers in either orientation (for example) V linked by 5 or 10 amino acids or linked without any linkers H and VL domains; for example, as described in U.S. Patent No. 5,844,094. Trimers and tetramers; for example, as described in U.S. Patent No. 5,864,019. A crosslinkable group formed by a VL domain that further associates with a series of FV (or scFv) at the C-terminus VH domain (or family member) linked by peptide bond accompanied by A sequence of VL domains; and, for example, as described in U.S. Patent No. 5,869,620. As described above, homodivalent, he Polyvalent structures are formed via non-covalent or chemical crosslinking, creating divalent, trivalent, and tetravalent structures. It has both VH and VL domains linked via a compoundable peptide linker. Examples include, but are not limited to, single-stranded polypeptides. Additional exemplary polyploids Isomerous and bispecific molecules, as well as methods for producing them, are described, for example, in U.S. Patent No. 591057. U.S. Patent No. 3, U.S. Patent No. 5932448, U.S. Patent No. 5959083, U.S. Patent No. 5989830, U.S. Patent No. 6005079, U.S. Patent No. 6 U.S. Patent No. 239259, U.S. Patent No. 6294353, U.S. Patent No. 6333396 U.S. Patent No. 6476198, U.S. Patent No. 6511663, U.S. Japanese Patent No. 6670453, U.S. Patent No. 6743896, U.S. Patent No. 68 U.S. Patent No. 09185, U.S. Patent No. 6833441, U.S. Patent No. 7129330 Specification, U.S. Patent No. 7183076, U.S. Patent No. 7521056, United States Japanese Patent No. 7527787, U.S. Patent No. 7534866, U.S. Patent No. 761 Specifications No. 2181, U.S. Patent Application Publication No. 2002 / 004587A1, U.S. Patent U.S. Patent Application Publication No. 2002 / 076406A1, U.S. Patent Application Publication No. 2002 / 103 Specifications 345A1, U.S. Patent Application Publication No. 2003 / 207346A1, U.S. Patent Patent Application Publication No. 2003 / 211078A1, U.S. Patent Application Publication No. 2004 / 21 Specifications 9643A1, U.S. Patent Application Publication No. 2004 / 220388A1, United States Patent Application Publication No. 2004 / 242847A1, U.S. Patent Application Publication No. 2005 / 0 Specification No. 03403A1, U.S. Patent Application Publication No. 2005 / 004352A1, U.S. National Patent Application Publication No. 2005 / 069552A1, U.S. Patent Application Publication No. 2005 / Specification No. 079170A1, U.S. Patent Application Publication No. 2005 / 100543A1, U.S. Patent Application Publication No. 2005 / 136049A1, U.S. Patent Application Publication No. 2005 Specification No. / 136051A1, U.S. Patent Application Publication No. 2005 / 163782A1 , U.S. Patent Application Publication No. 2005 / 266425A1 specification, U.S. Patent Application Publication No. 200 Specification No. 6 / 083747A1, U.S. Patent Application Publication No. 2006 / 120960A1 The document, U.S. Patent Application Publication No. 2006 / 204493A1, U.S. Patent Application Publication No. 20 Specification No. 06 / 263367A1, U.S. Patent Application Publication No. 2007 / 004909A1 Detailed description, U.S. Patent Application Publication No. 2007 / 087381A1 specification, U.S. Patent Application Publication No. 2 Specification No. 007 / 128150A1, U.S. Patent Application Publication No. 2007 / 141049A1 Specification, U.S. Patent Application Publication No. 2007 / 154901A1, U.S. Patent Application Publication No. Specification No. 2007 / 274985A1, U.S. Patent Application Publication No. 2008 / 050370A1 Specifications, U.S. Patent Application Publication No. 2008 / 069820A1, U.S. Patent Application Publication Specification No. 2008 / 152645A1, U.S. Patent Application Publication No. 2008 / 171855A Specification No. 1, U.S. Patent Application Publication No. 2008 / 241884A1, U.S. Patent Application Publication Specifications of Patent Application No. 2008 / 254512A1, U.S. Patent Application Publication No. 2008 / 260738 Specification A1, U.S. Patent Application Publication No. 2009 / 130106A1, U.S. Patent Application Published specification No. 2009 / 148905A1, U.S. Patent Application Publication No. 2009 / 15527 Specifications 5A1, U.S. Patent Application Publication No. 2009 / 162359A1, U.S. Patent Application Publication Specification of Patent Application Publication No. 2009 / 162360A1, U.S. Patent Application Publication No. 2009 / 1758 Specification 51A1, U.S. Patent Application Publication No. 2009 / 175867A1, U.S. Patent U.S. Patent Application Publication No. 2009 / 232811A1, U.S. Patent Application Publication No. 2009 / 234 Specification 105A1, U.S. Patent Application Publication No. 2009 / 263392A1, U.S. Patent Patent Application Publication No. 2009 / 274649A1, European Patent Application Publication No. 346087A Specification No. 2, Pamphlet International Publication No. 00 / 06605A2, International Publication No. 02 / 072 Pamphlet No. 635A2, International Publication No. 04 / 081051A1, International Publication Pamphlet No. 06 / 020258A2, International Publication No. 2007 / 044887A2 Pamphlet, International Publication No. 2007 / 095338A2 Pamphlet, International Publication No. 20 Pamphlet No. 07 / 137760A2, International Publication No. 2008 / 119353A1 Fret, International Publication No. 2009 / 021754A2 Pamphlet, International Publication No. 2009 Pamphlet No. / 068630A1, International Publication No. 91 / 03493A1, International Publication No. 93 / 23537A1, International Publication No. 94 / 09131A1 Pamphlet, International Publication No. 94 / 12625A2, International Publication No. 95 / 099 Pamphlet No. 17A1, International Publication No. 96 / 37621A2, International Publication No. This can be found in pamphlet 99 / 64460A1. The contents of the application referenced above are: This entire body is incorporated herein by reference.

[0119] In other embodiments, anti-galectins, such as anti-galectin-1 or anti-galectin-3, are used. Antibody molecules (e.g., monospecific, bispecific, or multispecific antibody molecules) are paired with another partner. - For example, covalently linked as proteins, for example, fusion molecules, for example, fusion proteins. , for example, they are fused. In one embodiment, the bispecific antibody molecule is a first target (for example) , first binding specificity to galectin-1, second target (e.g., galectin-3) It has a second binding specificity for [the specified element].

[0120] The present invention provides an isolated nucleic acid molecule encoding the aforementioned antibody molecule, its vector, and host cell. To provide. Nucleic acid molecules include RNA, genomic DNA, and cDNA, but these Not limited to this.

[0121] Cancer immunotherapy drugs Selected PD-1 inhibitors Programmed Death 1 (PD-1) protein is a T cell regulatory factor, and is related to the extended CD28 / CTLA -4 is an inhibitory member of the family (Okazaki et al. (2002) C urr Opin Immunol 14:391779-82;Bennett et. al. (2003) J.Immunol. 170:711-8). 2 for PD-1 Two ligands, PD-L1(B7-H1) and PD-L2(B7-DC), have been identified. Furthermore, it has been shown that binding to PD-1 downregulates T cell activation (F reeman et al.(2000)J.Exp.Med.192:1027-34 ;Carter et al.(2002)Eur.J.Immunol.32:634 -43). PD-L1 is abundant in various human cancers (Dong et al. 2002) Nat. Med. 8:787-9).

[0122] PD-1 is known as an immunosuppressive protein that negatively modulates TCR signaling. hida,Y.et al.(1992)EMBO J.11:3887-3895;B Lank,C.et al.(Epub 2006 Dec.29)Immunol.I mmunother.56(5):739-745). Phase between PD-1 and PD-L1. The interactions include, for example, a decrease in tumor-infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, and / or It acts as an immune checkpoint that can cause cancer cells to evade the immune system. This is possible (Dong et al. (2003) J.Mol.Med.81:281-7 ;Blank et al.(2005)Cancer Immunol.Immuno ther.54:307-314;Konishi et al.(2004)Clin (Cancer Res. 10:5094-100). PD-1 and PD-L1 or PD It is possible to reverse immunosuppression by inhibiting local interactions with L2. The effect is additive when the interaction between PD-1 and PD-L2 is also blocked (I wai et al.(2002)Proc.Nat'l.Acad.Sci.USA 99:12293-7;Brown et al.(2003)J.Immunol.1 70:1257-66).

[0123] In certain embodiments, the combinations described herein include a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is PDR001 (Novartis), Mubrolizumab (Merck & Co), Pidilizumab (CureTech), Durba Lomab, atezolizumab, avelumab, MEDI0680 (Medimmune), RE GN2810 (Regeneron), TSR-042 (Tesaro), PF-068 01591 (Pfizer), BGB-A317 (Beigene), BGB-108 ( Beigene), INCSHR1210 (Incyte) or AMP-224 (Amp Selected from (1) immunoglobulins. In some embodiments, the PD-1 inhibitor is PDR It is 001. PDR001 is also known as spartalizumab.

[0124] Exemplary PD-1 inhibitors In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule. Furthermore, PD-1 inhibitors, as a whole, are referred to as "Antibody Mol." 20 The specification of U.S. Patent Application Publication No. 2015 / 0210769, published on July 30, 2015, This is an anti-PD-1 antibody molecule described in [the relevant section]. In some embodiments, the anti-PD-1 antibody The molecule is spartalizumab (PDR001).

[0125] In one embodiment, the anti-PD-1 antibody molecule is one of those shown in Table 1 (for example, disclosed in Table 1). The heavy and light chain variable regions of BAP049-clone-E or BAP049-clone-B. (from the regional sequence) or the amino acid sequence encoded by the nucleotide sequence shown in Table 1 At least 1, 2, 3, 4, 5, or 6 complements derived from the heavy chain and light chain variable regions, including Includes the decision region (CDR) (or all CDRs collectively). In some embodiments, C DR follows the Kabat definition (for example, as described in Table 1). Partial implementation In terms of form, CDR is defined by Chothia (for example, as described in Table 1). ) conforms to. In some embodiments, CDR is both Kabat and Chothia ( For example, it follows the combined CDR definitions (as described in Table 1). In this state, the combination of VH CDR1 Kabat and Chothia CDRs is, It contains the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, C One or more DRs (or all CDRs collectively) have 1, 2, 3, 4, 5, or 6 or more changes. For example, as shown in Table 1, or by the nucleotide sequence shown in Table 1 Amino acid substitutions (e.g., conservative amino acid substitutions) or omissions in the encoded amino acid sequence. It has a loss.

[0126] In one embodiment, the anti-PD-1 antibody molecule is SEQ ID NO: 50, as disclosed in Table 1. The amino acid sequence of VHCDR1 of sequence 1, the amino acid sequence of VHCDR2 of sequence number 502, and sequence number The heavy chain variable region (VH) containing the VHCDR3 amino acid sequence of number 503, and SEQ ID NO: 51 VLCDR1 amino acid sequence of 0, VLCDR2 amino acid sequence of SEQ ID NO: 511 and sequence number It contains a light chain variable region (VL) including the VLCDR3 amino acid sequence of no. 512.

[0127] In one embodiment, the antibody molecule is the nucleotide of SEQ ID NO: 524, as disclosed in Table 1. The nucleotide sequence of VHCDR1, sequence number 525, is encoded by the Otid sequence. The nucleotide sequence of VHCDR2 and sequence number 526 is coded as follows: VH containing VHCDR3; and coded by the nucleotide sequence of SEQ ID NO: 529 VLCDR1, encoded by the nucleotide sequence of sequence number 530, is VLCD VLCDR3, which contains R2 and VLCDR3 encoded by the nucleotide sequence of SEQ ID NO: 531 Includes L.

[0128] In one embodiment, the anti-PD-1 antibody molecule is the amino acid sequence of SEQ ID NO: 506 or the sequence Amino acid sequences that are at least 85%, 90%, 95%, or 99% identical to number 506. VH containing the following is included. In one embodiment, the anti-PD-1 antibody molecule is the amine of SEQ ID NO: 520. The no acid sequence or sequence number 520 is identical to at least 85%, 90%, 95%, or 99% of the sequence. It contains a VL containing an amino acid sequence. In one embodiment, the anti-PD-1 antibody molecule is SEQ ID NO: 516 amino acid sequence or SEQ ID NO: 516 and at least 85%, 90%, 95%, or 99% Contains VL containing % or more identical amino acid sequences. In one embodiment, an anti-PD-1 antibody molecule This includes VH containing the amino acid sequence of SEQ ID NO: 506 and the amino acid sequence of SEQ ID NO: 520. Contains VL. In one embodiment, the anti-PD-1 antibody molecule has the amino acid configuration of SEQ ID NO: 506. It includes VH containing the column and VL containing the amino acid sequence of SEQ ID NO: 516.

[0129] In one embodiment, the antibody molecule is the nucleotide sequence of SEQ ID NO: 507 or SEQ ID NO: 5 By a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to 07 It contains VH which is coded as follows. In one embodiment, the antibody molecule is SEQ ID NO: 521 or 517 nucleotide sequences or at least 85% and 90% of sequence numbers 521 or 517 Contains VLs encoded by 95% or more identical nucleotide sequences. In one embodiment, the antibody molecule is encoded by the nucleotide sequence of SEQ ID NO: 507. Includes VH and VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517. nothing.

[0130] In one embodiment, the anti-PD-1 antibody molecule is the amino acid sequence of SEQ ID NO: 508 or the sequence Contains an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to number 508. It contains heavy chains. In one embodiment, the anti-PD-1 antibody molecule contains the amino acids of SEQ ID NO: 522. A net identical to sequence or sequence number 522 by at least 85%, 90%, 95%, or 99% or more. It contains a light chain containing an acid sequence. In one embodiment, the anti-PD-1 antibody molecule is SEQ ID NO 518 The amino acid sequence or sequence number 518 is at least 85%, 90%, 95%, or 99% identical. It contains a light chain containing a single amino acid sequence. In one embodiment, the anti-PD-1 antibody molecule contains a sequence It contains a heavy chain containing amino acid sequence number 508 and a light chain containing amino acid sequence number 522. In one embodiment, the anti-PD-1 antibody molecule comprises the amino acid sequence of SEQ ID NO: 508. It contains a heavy chain and a light chain containing the amino acid sequence of SEQ ID NO: 518.

[0131] In one embodiment, the antibody molecule is the nucleotide sequence of SEQ ID NO: 509 or SEQ ID NO: 5 By nucleotide sequences that are at least 85%, 90%, 95%, or 99% or more identical to 09 It contains a heavy chain encoded by . In one embodiment, the antibody molecule is sequence number 523 or 519 nucleotide sequences or at least 85% and 90% of sequence numbers 523 or 519 Contains light chains encoded by identical nucleotide sequences of %, 95%, or 99% or more. In one embodiment, the antibody molecule is encoded by the nucleotide sequence of SEQ ID NO: 509. It includes a heavy chain and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519. nothing.

[0132] The antibody molecules described herein are, in whole, referenced by the published U.S. patent application. By the vector, host cell and method described in Specification No. 2015 / 0210769 It can be manufactured.

[0133] [Table 1]

[0134] [Table 2]

[0135] [Table 3]

[0136] [Table 4]

[0137] [Table 5]

[0138] [Table 6]

[0139] [Table 7]

[0140] [Table 8]

[0141] In some embodiments, the PD-1 inhibitor is administered in a dose of approximately 200 mg to approximately 500 mg (for example, It is administered in doses of approximately 300 mg to 400 mg. In some embodiments, PD-1 The inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered every four weeks. It is administered once in between. In some embodiments, the PD-1 inhibitor is administered at a dose of approximately 200 mg to approximately 4 It is administered once every three weeks at a dose of 00 mg (for example, about 300 mg). Further embodiments In this case, PD-1 inhibitors are administered in doses of approximately 300 mg to approximately 500 mg (for example, approximately 400 mg). It is administered once every four weeks.

[0142] In some embodiments, the combination includes PD-1 inhibitors, such as PDR001 and T Includes a GF-β inhibitor, such as NIS793. In some embodiments, the combination is For example, it is administered to a patient in a therapeutically effective dose for treating pancreatic cancer.

[0143] In some embodiments, the combination includes PD-1 inhibitors, such as PDR001 and T Includes an LR7 agonist, such as LHC165. In some embodiments, the combination is For example, it is administered to a subject in a therapeutically effective dose for treating pancreatic cancer. In some embodiments, TLR7 agonists, such as LHC165, are administered via intratumor injection.

[0144] In some embodiments, the combination includes a PD-1 inhibitor, for example, PDR001 and This includes denosine receptor antagonists, such as PBF509 (NIR178). In terms of administration methods, the combination involves, for example, administering a therapeutically effective dose to a target for treating pancreatic cancer. To be given.

[0145] In some embodiments, the combination includes a PD-1 inhibitor, for example, PDR001 and PO This includes a cubine inhibitor, such as WNT974. In some embodiments, the combination For example, it is administered to the subject in a therapeutically effective dose for treating pancreatic cancer.

[0146] In some embodiments, the combination is a PD-1 inhibitor, for example, PDR001 and A Includes 2aR antagonists, such as PBF509 (NIR178). In some embodiments... In this context, the combination is, for example, administered to the target in a therapeutically effective dose for treating CRC or gastric cancer. It is given. Although not bound by theory, PD-1 inhibitors, such as PDR001 and Combinations containing A2aR antagonists, such as PBF509 (NIR178), are effective against This is thought to lead to an increase in the effectiveness of PD-1 inhibitors. In some embodiments, PD-1 inhibitors, e.g., PDR001 and A2aR antagonists, e.g., PBF509 The combination of (NIR178) leads to regression of CRC tumors.

[0147] In some embodiments, the combination is a PD-1 inhibitor, for example, PDR001 and P D-L1 inhibitors, such as FAZ053, are included. In some embodiments, the combination is For example, it is administered to a patient in a therapeutically effective dose for treating breast cancer, such as tetrafluoroenolytica (PLA)-negative breast cancer.

[0148] Other exemplary PD-1 inhibitors In one embodiment, the anti-PD-1 antibody molecule is lambrolizumab, MK-3475, M Also known as K03475, SCH-900475, or KEYTRUDA (registered trademark). This is pembrolizumab (Merck & Co). Pembrolizumab and other anti-PD-1 The antibody is referenced as a whole by Hamid, O. et al. (2013)N ew England Journal of Medicine 369(2):13 4-44, U.S. Patent No. 8,354,509 and International Publication No. 2009 / 11433 This is disclosed in Pamphlet No. 5. In one embodiment, the anti-PD-1 antibody molecule is, for example, One or more (or all) of the pembrolizumab CDR sequences as disclosed in Table 2. Includes a CDR sequence, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0149] In one embodiment, the anti-PD-1 antibody molecule is Pidiri, also known as CT-011. It is zumab (CureTech). Pidilizumab and other anti-PD-1 antibodies are overall Rosenblatt, J. et al. (2011) JI Mmunotherapy 34(5):409-18, U.S. 7,695,715 U.S. Patent No. 7,332,582 and U.S. Patent No. 8,686,119 Disclosed in the specification. In one embodiment, an anti-PD-1 antibody molecule is disclosed, for example, in Table 2. As described, one or more (or all) CDR sequences of pidilyzumab ), including a heavy chain or light chain variable region sequence or a heavy chain or light chain sequence.

[0150] In one embodiment, the anti-PD-1 antibody molecule is durvalomab.

[0151] In one embodiment, the anti-PD-1 antibody molecule is atezolizumab.

[0152] In one embodiment, the anti-PD-1 antibody molecule is avelumab.

[0153] In one embodiment, the anti-PD-1 antibody molecule is MED, also known as AMP-514. It is I0680 (Medimmune). MEDI0680 and other anti-PD-1 antibodies are , as a whole, U.S. Patent No. 9,205,148 and the International Publication, which are incorporated by reference. Disclosed in pamphlet No. 2012 / 145493. In one embodiment, anti-PD- 1. The antibody molecule contains one or more (or all) CDR sequences of MEDI0680. Includes a column, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0154] In one embodiment, the anti-PD-1 antibody molecule is REGN2810 (Regeneron In one embodiment, the anti-PD-1 antibody molecule is the CDR sequence of REGN2810. One or more of (or all CDR sequences collectively), heavy chain or light chain variable region sequences or heavy chain Alternatively, it may include a light chain sequence.

[0155] In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 (Pfizer ) In one embodiment, the anti-PD-1 antibody molecule is PF-06801591 CD One or more R sequences (or all CDR sequences collectively), heavy chain or light chain variable region sequences or It contains a heavy chain or light chain sequence.

[0156] In one embodiment, the anti-PD-1 antibody molecule is BGB-A317 or BGB-108( Beigene) In one embodiment, the anti-PD-1 antibody molecule is BGB-A31 One or more CDR sequences of 7 or BGB-108 (or all CDR sequences collectively), heavy chain Alternatively, it may include a light chain variable region sequence or a heavy chain or light chain sequence.

[0157] In one embodiment, the anti-PD-1 antibody molecule is INCSHR01210 or SHR-1 This is INCSHR1210 (Incyte), also known as 210. In one embodiment... Furthermore, the anti-PD-1 antibody molecule contains one or more (or a whole) CDR sequences of INCSHR1210. (including all CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or light chain sequences nothing.

[0158] In one embodiment, the anti-PD-1 antibody molecule is TSR-, also known as ANB011. 042 (Tesaro). In one embodiment, the anti-PD-1 antibody molecule is TSR- One or more of the 042 CDR sequences (or all of the CDR sequences collectively), heavy chain or light chain. It includes a variable region sequence or a heavy chain or light chain sequence.

[0159] Further known anti-PD-1 antibodies include, for example, the internationally recognized antibodies, which are referenced collectively. Pamphlet No. 2015 / 112800, International Publication No. 2016 / 092419 Brochure, International Publication No. 2015 / 085847, International Publication No. 2014 / Pamphlet No. 179664, International Publication No. 2014 / 194302, International Pamphlet No. 2014 / 209804, International Pamphlet No. 2015 / 200119 U.S. Patent No. 8,735,553, U.S. Patent No. 7,488,802 Specification, U.S. Patent No. 8,927,697, U.S. Patent No. 8,993,731 Examples include those described in the book and U.S. Patent No. 9,102,727.

[0160] In one embodiment, the anti-PD-1 antibody is one of the anti-PD-1 antibodies described herein. An antibody that competes for binding to the same epitope on PD-1 and / or binds to it. be.

[0161] In one embodiment, the PD-1 inhibitor is, for example, a rice grain that is referenced as a whole. The PD-1 signaling pathway as described in Japanese Patent No. 8,907,053 It is an inhibitory peptide. In one embodiment, the PD-1 inhibitor is an immunoadhesin ( For example, PD-L1 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence) (This refers to an immunoadhesian containing the extracellular portion of PD-L2 or the PD-1 binding portion.) In one embodiment, the PD-1 inhibitor is AMP-224 (for example, by reference as a whole). International Publication No. 2010 / 027827 and International Publication No. 2011 / are referenced. B7-DCIg(Amplimmune)) disclosed in pamphlet No. 066342 be.

[0162] [Table 9]

[0163] Additional combination therapy In one embodiment, the combination is a PD-1 inhibitor (e.g., PDR001) and mTOR inhibitors, such as RAD001 (also known as everolimus). In the embodiment, the combination is PDR001 and an mTOR inhibitor, for example, RAD00 Includes 1. In some embodiments, the combination includes PDR001 and RAD001. In some embodiments, an mTOR inhibitor, such as RAD001, is present in a concentration of at least 0. 5mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg or It is administered once a week at a dose of 10 mg. In some embodiments, an mTOR inhibitor, for example RAD001 is administered once a week at a dose of 10 mg. In some embodiments, mT OR inhibitors, such as RAD001, are administered once a week at a dose of 5 mg. (Some embodiments) In this case, mTOR inhibitors, such as RAD001, are administered in doses of at least 0.5 mg, 1 mg, and 2 mg. In doses of mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg It is administered once daily. In some embodiments, an mTOR inhibitor, such as RAD001, is used. It is administered once daily at a dose of 0.5 mg. In some embodiments, the combination is, for example, For example, effective treatment for cancer, such as the cancers described herein, such as colorectal cancer. It is administered to the target in a specified quantity.

[0164] LAG-3 inhibitors In certain embodiments, the combinations described herein include a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is LAG525 (Novartis) , BMS-986016 (Bristol-Myers Squibb) or TSR-0 Select from 33 (Tesaro).

[0165] Exemplary LAG-3 inhibitors In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In this context, LAG-3 inhibitors are referred to as "Antibody" in the overall context. The name is "Molecules to LAG-3 and Uses Thereof". U.S. Patent Application Publication No. 2015 / 0259420, published on September 17, 2015. The anti-LAG-3 antibody molecule is as disclosed in the specification.

[0166] In one embodiment, the anti-LAG-3 antibody molecule is one of those shown in Table 5 (for example, open in Table 5) The heavy and light chains of the indicated BAP050-clone-I or BAP050-clone-J are variable. (from the region sequence) or the amino acid sequence encoded by the nucleotide sequence shown in Table 5 At least 1, 2, 3, 4, 5, or 6 complementary chains derived from the heavy and light chain variable regions including the columns. Includes the sex determination region (CDR) (or all CDRs collectively). In some embodiments, CDR follows the Kabat definition (for example, as described in Table 5). Some actual In terms of application methods, CDR is defined by Chothia (for example, as described in Table 5). In some embodiments, the CDR is based on both Kabat and Chothia. The combined CDR definitions (as shown in Table 5, for example) are followed. In terms of form, the combination of VH CDR1 Kabat and Chothia CDRs is , containing the amino acid sequence GFTLTNYGMN (SEQ ID NO: 766). In one embodiment, One or more CD-Rs (or all CD-Rs collectively) have 1, 2, 3, 4, 5, or 6 or more modifications. For example, by the nucleotide sequences shown in Table 5, or by the nucleotide sequences shown in Table 5. Amino acid substitutions (e.g., conservative amino acid substitutions) to the amino acid sequence encoded by or It has a defect.

[0167] In one embodiment, the anti-LAG-3 antibody molecule is SEQ ID NO: 7, as disclosed in Table 5. The amino acid sequence of VHCDR1 of 01, the amino acid sequence of VHCDR2 of SEQ ID NO: 702 and sequence Heavy chain variable region (VH) containing amino acid sequence number 703 (VHCDR3); and Sequence ID No. 7 10 VLCDR1 amino acid sequences, VLCDR2 amino acid sequence of SEQ ID NO: 711 and sequence It contains a light chain variable region (VL) that includes the VLCDR3 amino acid sequence number 712.

[0168] In one embodiment, the anti-LAG-3 antibody molecule is SEQ ID NO: 7, as disclosed in Table 5. VHCDR1, sequence number 738, encoded by a nucleotide sequence of 36 or 737. or VHCDR2 and SEQ ID NO: 740 encoded by the nucleotide sequence of 739 VH contains VHCDR3 encoded by a sequence of 741 nucleotides; and the sequence VLCDR1, 748 or 747, encoded by the nucleotide sequence number 746 or 747 VLCDR2, encoded by the nucleotide sequence of 749, 750, or 751 The VL includes VLCDR3 encoded by a creotide sequence. In one embodiment, The anti-LAG-3 antibody molecules are those of Sequence ID No. 758 or 737, respectively, as disclosed in Table 5. Nucleotypes of VHCDR1, sequence number 759 or 739, encoded by a creotide sequence VHCDR2 and nucleo of sequence number 760 or 741 encoded by the Otid sequence VH containing VHCDR3 encoded by the cydone sequence; and sequence numbers 746 or 74 The nucleo of VLCDR1, 748, or 749 encoded by the nucleotide sequence of 7 The nucleotides of VLCDR2, sequence number 750 or 751, encoded by the cydoid sequence Includes a VL containing VLCDR3 encoded by an array.

[0169] In one embodiment, the anti-LAG-3 antibody molecule has the amino acid sequence of SEQ ID NO: 706 or amino acid sequences that are at least 85%, 90%, 95%, or 99% identical to sequence number 706 Contains VH. In one embodiment, the anti-LAG-3 antibody molecule is amine of SEQ ID NO: 718. The no-acid sequence or is at least 85%, 90%, 95%, or 99% identical to sequence number 718. It contains a VL containing an amino acid sequence. In one embodiment, the anti-LAG-3 antibody molecule contains a sequence number The amino acid sequence of number 724 or sequence number 724 and at least 85%, 90%, 95%, or 9% Contains VH with more than 9% identical amino acid sequence. In one embodiment, an anti-LAG-3 antibody The molecule contains at least 85% to 90% of the amino acid sequence of SEQ ID NO: 730 or SEQ ID NO: 730. , containing VL which has 95% or 99% or more identical amino acid sequences. In one embodiment, anti The LAG-3 antibody molecule contains the amino acid sequence of SEQ ID NO: 706 (VH) and SEQ ID NO: 718. It contains a VL containing an amino acid sequence. In one embodiment, the anti-LAG-3 antibody molecule contains a sequence number Includes VH containing the amino acid sequence of number 724 and VL containing the amino acid sequence of SEQ ID NO: 730. .

[0170] In one embodiment, the antibody molecule has the nucleotide sequence of SEQ ID NO: 707 or 708. Or at least 85%, 90%, 95%, or 99% or more of sequence number 707 or 708. It contains VH encoded by the same nucleotide sequence. In one embodiment, antibody The child is the nucleotide sequence of sequence number 719 or 720 or sequence number 719 or 7 By nucleotide sequences that are at least 85%, 90%, 95%, or 99% or more identical to 20. It includes VL which is coded by. In one embodiment, the antibody molecule is SEQ ID NO: 725 or 726 nucleotide sequences or at least 85% and 90% of sequence numbers 725 or 726 Contains VH encoded by 95% or more identical nucleotide sequences. In this embodiment, the antibody molecule has the nucleotide sequence of SEQ ID NO: 731 or 732 or Sequence ID 731 or 732 is at least 85%, 90%, 95%, or 99% identical. It contains a VL encoded by a nucleotide sequence. In one embodiment, the antibody molecule , VH and SEQ ID NO: encoded by the nucleotide sequence of SEQ ID NO: 707 or 708 It includes a VL encoded by a nucleotide sequence of 719 or 720. In one embodiment, The antibody molecule is encoded by the nucleotide sequence of SEQ ID NO: 725 or 726. Includes VH and VL encoded by the nucleotide sequence of SEQ ID NO: 731 or 732. .

[0171] In one embodiment, the anti-LAG-3 antibody molecule has the amino acid sequence of SEQ ID NO: 709 or amino acid sequences that are at least 85%, 90%, 95%, or 99% identical to sequence number 709 Contains heavy chains. In one embodiment, the anti-LAG-3 antibody molecule contains the amine of SEQ ID NO: 721. The no acid sequence or sequence number 721 is at least 85%, 90%, 95%, or 99% identical to it. It contains a light chain containing an amino acid sequence. In one embodiment, the anti-LAG-3 antibody molecule contains a light chain containing an amino acid sequence. The amino acid sequence of number 727 or sequence number 727 and at least 85%, 90%, 95%, or 9% It contains a heavy chain with 9% or more identical amino acid sequences. In one embodiment, an anti-LAG-3 antibody The molecule contains at least 85% to 90% of the amino acid sequence of SEQ ID NO: 733 or SEQ ID NO: 733. , comprising a light chain containing 95% or 99% or more identical amino acid sequences. In one embodiment, anti The LAG-3 antibody molecule contains a heavy chain with the amino acid sequence of SEQ ID NO: 709 and SEQ ID NO: 721. It contains a light chain containing an amino acid sequence. In one embodiment, the anti-LAG-3 antibody molecule contains a light chain containing an amino acid sequence. Includes a heavy chain containing the amino acid sequence of number 727 and a light chain containing the amino acid sequence of sequence number 733. .

[0172] In one embodiment, the antibody molecule has the nucleotide sequence of SEQ ID NO: 716 or 717. Or at least 85%, 90%, 95%, or 99% or more of sequence number 716 or 717 It contains a heavy chain encoded by the same nucleotide sequence. In one embodiment, the antibody molecule , the nucleotide sequence of sequence number 722 or 723 or sequence number 722 or 723 And by having a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical It contains a light chain that is linked. In one embodiment, the antibody molecule is SEQ ID NO: 728 or 72 9 nucleotide sequences or sequence numbers 728 or 729 and at least 85%, 90%, Contains a heavy chain encoded by 95% or 99% or more identical nucleotide sequences. Morphologically, the antibody molecule is the nucleotide sequence of SEQ ID NO: 734 or 735 or sequence Number 734 or 735 is identical to at least 85%, 90%, 95%, or 99% or more of the original number. It contains a light chain encoded by a creotide sequence. In one embodiment, the antibody molecule is distributed The heavy chain encoded by the nucleotide sequence of sequence number 716 or 717 and SEQ ID NO: 72 It comprises a light chain encoded by a sequence of 2 or 723 nucleotides. In one embodiment, The antibody molecule is a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 728 or 729. and includes a light chain encoded by the nucleotide sequence of SEQ ID NO: 734 or 735.

[0173] The antibody molecules described herein are, in whole, referenced by the published U.S. patent application. By the vector, host cell and method described in Specification No. 2015 / 0259420 It can be manufactured.

[0174] [Table 10]

[0175] [Table 11]

[0176] [Table 12]

[0177] [Table 13]

[0178] [Table 14]

[0179] [Table 15]

[0180] [Table 16]

[0181] [Table 17]

[0182] [Table 18]

[0183] [Table 19]

[0184] [Table 20]

[0185] [Table 21]

[0186] In some embodiments, LAG-3 inhibitors (e.g., anti-LAG inhibitors described herein) are used. -3 antibody molecules) are approximately 300-1000 mg, for example, approximately 300 mg to approximately 500 mg, approximately 4 It is administered in doses of 00 mg to approximately 800 mg or approximately 700 mg to approximately 900 mg. Embodiment In this context, LAG-3 inhibitors are administered once a week, once every two weeks, once every three weeks, once every four weeks, It is administered once every 5 weeks or once every 6 weeks. In the embodiment, the LAG-3 inhibitor is 3 It is administered once a week. In this embodiment, the LAG-3 inhibitor is administered once every four weeks. In other embodiments, the LAG-3 inhibitor is administered in doses of approximately 300 mg to approximately 500 mg (for example). It is administered once every three weeks at a dose of approximately 400 mg. In other embodiments, PD- 1. The inhibitor is administered at a dose of approximately 700 mg to 900 mg (for example, approximately 800 mg) every 4 weeks. It is administered once. In other embodiments, the LAG-3 inhibitor is administered in doses of approximately 400 mg to approximately 80 mg. It is administered once every four weeks at a dose of 0 mg (for example, approximately 600 mg).

[0187] In some embodiments, the composition, LAG-3 inhibitor, for example, as described herein LAG-3 inhibitors and PD-1 inhibitors, including, for example, the PD-1 inhibitors described herein. In some embodiments, the combination of a LAG-3 inhibitor and a PD-1 inhibitor is fixed. It is administered in a therapeutically effective dose to patients with tumors such as breast cancer, for example, tertiary negative breast cancer. (Theory) Although not restricted by this, combinations including LAG-3 inhibitors and PD-1 inhibitors are It is thought to have increased activity compared to the administration of PD-1 inhibitors alone.

[0188] In some embodiments, the composition, LAG-3 inhibitor, for example, as described herein LAG-3 inhibitors, GITR agonists, such as the GITR agonists described herein. and PD-1 inhibitors, including, for example, the PD-1 inhibitors described herein. Morphologically, combinations of LAG-3 inhibitors, GITR agonists, and PD-1 inhibitors. It is administered in a therapeutically effective dose to subjects with solid tumors, such as breast cancer, such as 3-negative breast cancer. In some embodiments, LAG-3 inhibitors, GITR agonists, and PD-1 inhibitors are used. Combinations including these may result in increased IL-2 production.

[0189] Other exemplary LAG-3 inhibitors In one embodiment, the anti-LAG-3 antibody molecule is also known as BMS986016. This is BMS-986016 (Bristol-Myers Squibb). 986016 and other anti-LAG-3 antibodies are referenced collectively by the International Publication No. This information is presented in Brochure No. 2015 / 116539 and U.S. Patent No. 9,505,839. As shown. In one embodiment, the anti-LAG-3 antibody molecule is disclosed, for example, in Table 6. One or more (or all) CDR sequences of BMS-986016 , including heavy chain or light chain variable region sequences or heavy chain or light chain sequences.

[0190] In one embodiment, the anti-LAG-3 antibody molecule is TSR-033(Tesaro) In one embodiment, the anti-LAG-3 antibody molecule is one of the CDR sequences of TSR-033. The above (or all CDR sequences collectively), heavy chain or light chain variable region sequences, or heavy chain or It contains a light chain sequence.

[0191] In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK283178 1 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 The antibodies are referenced in their entirety in International Publication No. 2008 / 132601. Disclosed in the U.S. Patent No. 9,244,059. In one embodiment, The LAG-3 antibody molecule is, for example, the CDR sequence of IMP731 as disclosed in Table 6. One or more (or all CDR sequences collectively), heavy chain or light chain variable region sequences, or heavy chain or light chain sequence. In one embodiment, the anti-LAG-3 antibody molecule is GSK2831 One or more of the 781 CDR sequences (or all of the CDR sequences collectively), heavy chain or light chain. It includes a variable region sequence or a heavy chain or light chain sequence.

[0192] In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioM In one embodiment, the anti-LAG-3 antibody molecule is a CDR compound of IMP761. One or more columns (or all CDR sequences collectively), heavy chain or light chain variable region sequences or heavy chain Includes chain or light chain sequences.

[0193] Further known anti-LAG-3 antibodies include, for example, the country referred to as a whole. International Publication No. 2008 / 132601, International Publication No. 2010 / 019570 Brochure, International Publication No. 2014 / 140180, Brochure, International Publication No. 2015 Pamphlet No. 116539, International Publication No. 2015 / 200119, Country International Publication No. 2016 / 028672, U.S. Patent No. 9,244,059 Examples include those described in the book and U.S. Patent No. 9,505,839.

[0194] In one embodiment, the anti-LAG-3 antibody is the anti-LAG-3 antibody described herein. One that competes for binding to the same epitope on LAG-3 and / or binds to it. It is an antibody.

[0195] In one embodiment, an anti-LAG-3 inhibitor is, for example, referenced as a whole. Soluble LAG- disclosed in International Publication No. 2009 / 044273 3. Proteins, for example, IMP321 (Prima BioMed).

[0196] [Table 22]

[0197] TIM-3 inhibitor In certain embodiments, the combinations described herein include a TIM-3 inhibitor. Hmm. Although not bound by theory, TIM-3 is The Cancer Genome Correlates with tumor bone marrow signatures in the e Atlas (TCGA) database, normal TIM-3, which is most abundant on peripheral blood mononuclear cells (PBMCs), is thought to be present on bone marrow cells. TIM-3 includes, but is not limited to, monocytes, macrophages, and dendritic cells. It is expressed in multiple bone marrow subsets in human PBMCs.

[0198] Tumor purity can be estimated from several TCGA tumor samples (e.g., adrenocortical carcinoma (ACC), bladder Bladder urothelial carcinoma (BLCA), invasive breast cancer (BRCA), cervical squamous cell carcinoma and cervix Adenocarcinoma (CESC), colorectal adenocarcinoma (COAD), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma ( HNSC), renal chromophilia (KICH), clear cell carcinoma (KIRC), papillary renal cell carcinoma (KIR) P), low-grade brain glioma (LGG), hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung Squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), prostate adenocarcinoma (PRAD), rectal Adenocarcinoma (READ), cutaneous melanoma (SKCM), thyroid cancer (THCA), uterine corpus endometrium TIM-3 expression is negatively correlated with cancer (including UCEC and uterine sarcoma (UCS)), This suggests that TIM-3 expression in tumor samples originates from tumor infiltrates.

[0199] In certain embodiments, the combination is used to treat kidney cancer (e.g., clear cell carcinoma (KI)). Treat RC) or papillary renal cell carcinoma (KIRP). In other embodiments, combination Using this method, brain tumors (e.g., low-grade glioma (LGG) or glioblastoma multiforme (GBM)) ) to treat. In some embodiments, a combination is used to treat mesothelioma (MESO) Treat. In some embodiments, a combination is used to treat sarcoma (SARC), lung adenocarcinoma. Treats lupus pulmonary adenomatous dysplasia (LUAD), pancreatic adenocarcinoma (PAAD), or lupus pulmonary squamous cell carcinoma (LUSC).

[0200] While not bound by theory, in some embodiments, immunosignature By clustering the indicators, the combinations described herein can be effectively Cancers that can be treated are, for example, those that are above the 75th percentile for each index in the TCGA as a whole. It is thought that this can be identified by determining the proportion of patients in that area.

[0201] In some embodiments, the T cell gene signature is CD2, CD247, CD3 D, CD3E, CD3G, CD8A, CD8B, CXCR6, GZMK, PYHIN1, Includes expression of one or more (e.g., all) of SH2D1A, SIRPG, or TRAT1.

[0202] In some embodiments, the bone marrow gene signature is SIGLEC1, MSR1, L Includes expression of one or more (e.g., all) of ILRB4, ITGAM, or CD163.

[0203] In some embodiments, the TIM-3 gene signature is HAVCR2, ADGR G1, PIK3AP1, CCL3, CCL4, PRF1, CD8A, NKG7, or KLR Includes expression of one or more K1 genes (e.g., all of them).

[0204] While not bound by theory, in some embodiments, TIM-3 inhibitors, for example MBG453 is a PD-1 inhibitor in mixed lymphocyte reaction (MLR) assays, for example It is thought to exhibit a synergistic effect with PDR001. In some embodiments, PD-L1 and Inhibition of TIM-3 leads to tumor reduction and survival in some mouse models of cancer. In this embodiment, inhibition of PD-L1 and LAG-3 is used in a mouse model of cancer to control tumors. It leads to reduction and survival.

[0205] In some embodiments, a combination is used to obtain TIM-3 and bone marrow signature High levels of one or more genes (for example, one or more genes expressed in macrophages) To treat cancers exhibiting Bell's expression. In some embodiments, TIM-3 and bone marrow signature Cancers with high levels of Char gene expression include sarcomas (SARC), mesothelioma (MESO), Brain tumors (e.g., glioblastoma (GBM)) or kidney cancer (e.g., papillary renal cell carcinoma (KIRP)) ) are selected from. In other embodiments, a combination is used to select TIM-3 and T. One or more cell signature genes (for example, expressed in dendritic cells and / or T cells) To treat cancers having high levels of expression of one or more genes. In some embodiments, Cancers exhibiting high levels of TIM-3 and T cell signature gene expression include renal cancer (e.g.) For example, clear cell renal carcinoma (KIRC), lung cancer (for example, lung adenocarcinoma (LUAD)), pancreatic adenocarcinoma (P) The diagnosis is selected from AAD (adverse adenomatous cancer) or testicular cancer (e.g., testicular germ cell tumor (TGCT)).

[0206] While not bound by theory, in some embodiments, immunosignature By clustering the indicators, two, three or more indicators described herein can be obtained. Cancers that can be effectively treated by targeting combinations include, for example, both targets or Identified by determining the proportion of patients exceeding the 75th percentile in all categories. It is possible.

[0207] In some embodiments, the combination is a TIM-3 inhibitor (e.g., as described herein). TIM-3 inhibitors (and PD-1 inhibitors as described herein) and PD-1 inhibitors (for example, PD-1 inhibitors as described herein) Inhibitors) are included, for example, for kidney cancer (e.g., papillary renal cell carcinoma (KIRC) or papillary renal cell carcinoma ( KIRP), mesothelioma (MESO), lung cancer (e.g., adenocarcinoma of the lung (LUAD) or squamous cell carcinoma of the lung) Cancer (LUSC), sarcoma (SARC), testicular cancer (e.g., testicular germ cell tumor (TGCT)) , pancreatic cancer (e.g. pancreatic adenocarcinoma (PAAD)), cervical cancer (e.g. cervical squamous cell carcinoma and and cervical adenocarcinoma (CESC)), head and neck cancer (e.g. head and neck squamous cell carcinoma (HNSC)), Bladder cancer (e.g., urothelial carcinoma of the bladder (BLCA)), gastric cancer (e.g., adenocarcinoma of the stomach (STAD)) , skin cancer (e.g., cutaneous melanoma (SKCM)), breast cancer (e.g., invasive breast cancer (BRCA)) The treatment involves treating cancer selected from ) or cholangiocarcinoma (CHOL).

[0208] In some embodiments, the combination is a TIM-3 inhibitor (e.g., as described herein). TIM-3 inhibitors (and LAG-3 inhibitors as described herein) and LAG-3 inhibitors (for example, LAG -3 inhibitors) are included, for example, in kidney cancer (e.g., papillary renal cell carcinoma (KIRC)), mesothelioma (M ESO), lung cancer (e.g., adenocarcinoma of the lung (LUAD) or squamous cell carcinoma of the lung (LUSC)), sarcoma ( SARC), testicular cancer (e.g., testicular germ cell tumor (TGCT)), cervical cancer (e.g., uterine cancer) Cervical squamous cell carcinoma and adenocarcinoma (CESC)), ovarian cancer (OV), head and neck cancer (e.g. Head and neck squamous cell carcinoma (HNSC), gastric cancer (for example, gastric adenocarcinoma (STAD)), bladder cancer (for example) For example, urothelial carcinoma of the bladder (BLCA), breast cancer (e.g., invasive breast cancer (BRCA)), or skin cancer. Treat cancers selected from among cancers (e.g., cutaneous melanoma (SKCM)).

[0209] In some embodiments, the combination is a TIM-3 inhibitor (e.g., as described herein). TIM-3 inhibitors (e.g., PD-1 inhibitors as described herein), PD-1 inhibitors (e.g., PD-1 inhibitors as described herein) A toxic agent and a LAG-3 inhibitor (for example, a LAG-3 inhibitor as described herein) are included. For example, kidney cancer (e.g., papillary renal cell carcinoma (KIRC)), lung cancer (e.g., lung adenocarcinoma (LUA)) D) or squamous cell carcinoma of the lung (LUSC), mesothelioma (MESO), testicular cancer (e.g., testicular cell carcinoma) Cholecystic tumors (TGCT), sarcomas (SARC), cervical cancer (e.g., squamous cell carcinoma of the cervix and cervical adenocarcinoma (CESC)), head and neck cancer (e.g. head and neck squamous cell carcinoma (HNSC)), gastric Cancer (e.g., gastric adenocarcinoma (STAD)), ovarian cancer (OV), bladder cancer (e.g., urothelial carcinoma of the bladder) (BLCA), breast cancer (e.g., invasive breast cancer (BRCA)), or skin cancer (e.g., melaninosis). We treat cancers selected from chromomas (SKCM).

[0210] In some embodiments, the combination is a TIM-3 inhibitor (e.g., as described herein). TIM-3 inhibitors (e.g., PD-1 inhibitors as described herein), PD-1 inhibitors (e.g., PD-1 inhibitors as described herein) A toxic agent and a c-MET inhibitor (for example, a c-MET inhibitor as described herein) are included. For example, kidney cancer (e.g., papillary renal cell carcinoma (KIRC)), lung cancer (e.g., lung adenocarcinoma (LUA)) Treatment is performed for cancer selected from D)) or mesothelioma (MESO).

[0211] In some embodiments, the TIM-3 inhibitor is MBG453 (Novartis) or This is TSR-022 (Tesaro). In some embodiments, it is a TIM-3 inhibitor. It is MBG453.

[0212] Exemplary TIM-3 inhibitors In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In this context, TIM-3 inhibitors are referred to as "Antibody" in their entirety. The name is "Molecules to TIM-3 and Uses Thereof". U.S. Patent Application Publication No. 2015 / 0218274, published on August 6, 2015. This is an anti-TIM-3 antibody molecule disclosed in the detailed document.

[0213] In one embodiment, the anti-TIM-3 antibody molecule is one of those shown in Table 7 (for example, open in Table 7) The heavy and light chain variable regions of ABTIM3-hum11 or ABTIM3-hum03 shown. (from the regional sequence) or the amino acid sequence encoded by the nucleotide sequence shown in Table 7 At least 1, 2, 3, 4, 5, or 6 complements derived from the heavy chain and light chain variable regions, including Includes the decision region (CDR) (or all CDRs collectively). In some embodiments, C DR follows the Kabat definition (for example, as described in Table 7). Partial implementation In terms of form, CDR is defined by Chothia (for example, as described in Table 7). ) in accordance with one embodiment, one or more (or all CDRs collectively) of the CDRs are 1 , 2, 3, 4, 5, 6 or more changes, for example, as shown in Table 7, or in Table 7 Amino acid substitutions for the amino acid sequence encoded by the nucleotide sequence shown (e.g.) For example, it has a conservative amino acid substitution (or deletion).

[0214] In one embodiment, the anti-TIM-3 antibody molecule is SEQ ID NO: 8, disclosed in Table 7. The amino acid sequence of VHCDR1 of 01, the amino acid sequence of VHCDR2 of SEQ ID NO: 802 and sequence Heavy chain variable region (VH) containing amino acid sequence number 803 (VHCDR3); and Sequence ID No. 8 10 VLCDR1 amino acid sequences, VLCDR2 amino acid sequence of SEQ ID NO: 811 and sequence Includes a light chain variable region (VL) containing the VLCDR3 amino acid sequence number 812. One embodiment In this study, the anti-TIM-3 antibody molecules are VHCs of SEQ ID NO: 801, as disclosed in Table 7. The amino acid sequence of DR1, the amino acid sequence of VHCDR2 of SEQ ID NO: 820, and SEQ ID NO: 803 The heavy chain variable region (VH) containing the VHCDR3 amino acid sequence, and VLC of SEQ ID NO: 810. The DR1 amino acid sequence, the VLCDR2 amino acid sequence of SEQ ID NO: 811, and SEQ ID NO: 812 It contains a light chain variable region (VL) that includes the VLCDR3 amino acid sequence.

[0215] In one embodiment, the anti-TIM-3 antibody molecule has the amino acid sequence of SEQ ID NO: 806 or amino acid sequences that are at least 85%, 90%, 95%, or 99% identical to sequence number 806 Contains VH. In one embodiment, the anti-TIM-3 antibody molecule is ami, of SEQ ID NO: 816. The no-acid sequence or is at least 85%, 90%, 95%, or 99% identical to sequence number 816. It contains a VL containing an amino acid sequence. In one embodiment, the anti-TIM-3 antibody molecule contains a sequence number The amino acid sequence of number 822 or sequence number 822 and at least 85%, 90%, 95%, or 9% Contains VH with an identical amino acid sequence of 9% or more. In one embodiment, an anti-TIM-3 antibody The molecule contains at least 85% to 90% of the amino acid sequence of SEQ ID NO: 826 or SEQ ID NO: 826. , containing VL which has 95% or 99% or more identical amino acid sequences. In one embodiment, anti The TIM-3 antibody molecule contains the amino acid sequence of SEQ ID NO: 806 (VH) and SEQ ID NO: 816. It contains a VL containing an amino acid sequence. In one embodiment, the anti-TIM-3 antibody molecule is SEQ ID NO: 8 It contains VH, which has 22 amino acid sequences, and VL, which has the amino acid sequence of SEQ ID NO: 826.

[0216] In one embodiment, the antibody molecule is the nucleotide sequence of SEQ ID NO: 807 or SEQ ID NO: 8 By a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to 07 It contains VH, which is coded as follows: In one embodiment, the antibody molecule contains the nucleus of SEQ ID NO: 817. The Otid sequence or sequence number 817 is identical by at least 85%, 90%, 95%, or 99% or more. It contains a VL encoded by a nucleotide sequence. In one embodiment, the antibody molecule , the nucleotide sequence of SEQ ID NO: 823 or at least 85%, 90%, Contains VH encoded by nucleotide sequences that are 95% or 99% or more identical. Morphologically, the antibody molecule has the nucleotide sequence of SEQ ID NO: 827 or a small amount of SEQ ID NO: 827. Even if not, coding is done by nucleotide sequences that are 85%, 90%, 95%, or 99% or more identical. It contains VL. In one embodiment, the antibody molecule has the nucleotide sequence of SEQ ID NO: 807. The VH sequence encoded by the column and the nucleotide sequence of sequence number 817 are encoded It contains VL. In one embodiment, the antibody molecule has the nucleotide sequence of SEQ ID NO: 823 Therefore, VH is encoded and V is encoded by the nucleotide sequence of sequence number 827. Includes L.

[0217] In one embodiment, the anti-TIM-3 antibody molecule has the amino acid sequence of SEQ ID NO: 808 or amino acid sequences that are at least 85%, 90%, 95%, or 99% identical to sequence number 808. Contains heavy chains. In one embodiment, the anti-TIM-3 antibody molecule is amine of SEQ ID NO: 818. The no-acid sequence or is at least 85%, 90%, 95%, or 99% identical to sequence number 818. It contains a light chain containing an amino acid sequence. In one embodiment, the anti-TIM-3 antibody molecule contains a light chain containing an amino acid sequence. The amino acid sequence of number 824 or at least 85%, 90%, 95%, or 9% of the sequence of number 824. It contains a heavy chain with more than 9% identical amino acid sequences. In one embodiment, an anti-TIM-3 antibody The molecule contains at least 85% to 90% of the amino acid sequence of SEQ ID NO: 828 or SEQ ID NO: 828. , comprising a light chain containing 95% or 99% or more identical amino acid sequences. In one embodiment, anti The TIM-3 antibody molecule contains a heavy chain with the amino acid sequence of SEQ ID NO: 808 and SEQ ID NO: 818. It contains a light chain containing an amino acid sequence. In one embodiment, the anti-TIM-3 antibody molecule contains a light chain containing an amino acid sequence. Includes a heavy chain containing the amino acid sequence of sequence number 824 and a light chain containing the amino acid sequence of sequence number 828. .

[0218] In one embodiment, the antibody molecule is the nucleotide sequence of SEQ ID NO: 809 or SEQ ID NO: 8 By nucleotide sequences that are at least 85%, 90%, 95%, or 99% or more identical to 09 It contains a heavy chain encoded by . In one embodiment, the antibody molecule contains the nucleus of SEQ ID NO: 819 The Otid sequence or sequence number 819 is identical by at least 85%, 90%, 95%, or 99% or more. It contains a light chain encoded by a nucleotide sequence. In one embodiment, the antibody molecule , the nucleotide sequence of SEQ ID NO: 825 or at least 85%, 90%, Contains a heavy chain encoded by 95% or 99% or more identical nucleotide sequences. Morphologically, the antibody molecule has the nucleotide sequence of SEQ ID NO: 829 or a small amount of SEQ ID NO: 829. Even if not, coding is done by nucleotide sequences that are 85%, 90%, 95%, or 99% or more identical. It contains a light chain. In one embodiment, the antibody molecule has a nucleotide sequence of SEQ ID NO: 809. The heavy chain encoded by the column and the nucleotide sequence of SEQ ID NO: 819 are encoded It contains a light chain. In one embodiment, the antibody molecule has the nucleotide sequence of SEQ ID NO: 825 Therefore, the heavy chain encoded and the light chain encoded by the nucleotide sequence of SEQ ID NO: 829 Includes chains.

[0219] The antibody molecules described herein are, in whole, referenced by the published U.S. patent application. By the vector, host cell and method described in Specification No. 2015 / 0218274 It can be manufactured.

[0220] [Table 23]

[0221] [Table 24]

[0222] [Table 25]

[0223] [Table 26]

[0224] [Table 27]

[0225] In some embodiments, the TIM-3 inhibitor is administered in doses of approximately 50 mg to 100 mg, or approximately 200 mg. mg to approximately 250 mg, approximately 500 mg to approximately 1000 mg, or approximately 1000 mg to approximately 1500 mg It is administered in a dose of g. In the embodiment, the TIM-3 inhibitor is administered once every four weeks. In other embodiments, the TIM-3 inhibitor is administered in doses of approximately 50 mg to approximately 100 mg. It is administered once a week. In other embodiments, the TIM-3 inhibitor is administered at approximately 200 mg to approximately The drug is administered once every four weeks at a dose of 250 mg. In other embodiments, a TIM-3 inhibitor is used. It is administered once every four weeks at a dose of approximately 500 mg to approximately 1000 mg. In other embodiments... TIM-3 inhibitors are administered once every four weeks at a dose of approximately 1000 mg to 1500 mg. It will be done.

[0226] Other exemplary TIM-3 inhibitors In one embodiment, the anti-TIM-3 antibody molecule is TSR-022(AnaptysBi (o / Tesaro). In one embodiment, the anti-TIM-3 antibody molecule is TSR-0 One or more of the 22 CDR sequences (or all of the CDR sequences collectively), heavy chain or light chain variable. It includes a regional sequence or a heavy chain or light chain sequence. In one embodiment, an anti-TIM-3 antibody molecule. For example, the CDR sequence of APE5137 or APE5121 as disclosed in Table 8. One or more of (or all CDR sequences collectively), heavy chain or light chain variable region sequences or heavy chain Or it contains a light chain sequence. APE5137, APE5121 and other anti-TIM-3 antibodies are This is referenced in the entirety in International Publication No. 2016 / 161270. It will be disclosed.

[0227] In one embodiment, the anti-TIM-3 antibody molecule is antibody clone F38-2E2. In one embodiment, the anti-TIM-3 antibody molecule contains one or more CDR sequences of F38-2E2. (or all CDR sequences collectively), heavy chain or light chain variable region sequences, or heavy chain or light chain Includes chain sequences.

[0228] Further known anti-TIM-3 antibodies include, for example, the country referred to as a whole. International Publication No. 2016 / 111947, International Publication No. 2016 / 071448 Pamphlet, International Publication No. 2016 / 144803, U.S. 8.55 U.S. Patent No. 2,156, U.S. Patent No. 8,841,418 and U.S. Patent No. 9,163 Examples include those described in Specification No. 087.

[0229] In one embodiment, the anti-TIM-3 antibody is the anti-TIM-3 antibody described herein. One competes for binding to the same epitope on TIM-3, and / or binds to it. It is an antibody.

[0230] [Table 28]

[0231] GITR Agonist Glucocorticoid-induced TNFR-related protein (GITR) is a tumor necrosis factor-soothing protein. It is a member of the Per family (TNFRSF). GITR expression increases further upon activation. It is constitutively detected in mouse and human CD4+CD25+ regulatory T cells that may be added. In contrast, effector CD4+CD25-T cells and CD8+CD25-T cells, It expresses GITRT at low to undetectable levels and rapidly upregulates after T cell receptor activation. GITR expression is also detected on activated NK cells, dendritic cells, and macrophages. The GITR signaling pathway is downstream of the MAPK and classical NFκB pathways. It has been shown to include various TRAF family members, GITR signaling It has been linked as a downstream intermediate (Nocentini et al. (200 5)Eur.J.Immunol.35:1016-1022).

[0232] Cell activation via GITR enhances cell type, proliferation, and effector function. This includes, however, protection from cell death induced by stimulation, inhibition of regulatory T cell suppression, and activation. It is thought to perform several functions that depend on the microenvironment, not limited to these (Sh evach and Stephens (2006) Nat. Rev. Immunol. 6:613-618). Agonist monoclonal antibodies against mouse GITR are used in tumors. Efficiently induce specific immunity and eradicate established tumors in mouse syngeneic tumor models. (Ko et al. (2005) J.Exp.Med.202:885-891) .

[0233] In certain embodiments, the combinations described herein involve a GITR agonist Includes. In some embodiments, the GITR agonist is GWN323(NVS), BM S-986156, MK-4166 or MK-1248 (Merck), TRX518 ( Leap Therapeutics), INCAGN1876(Incyte / Age From nus), AMG228 (Amgen), or INBRX-110 (Inhibrx) Selected.

[0234] Exemplary GITR agonist In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In this context, the GITR agonist is referred to as "Composit" as a whole. ions and Methods of Use for Augmented Im Two of them are named "Mune Response and Cancer Therapy" In the brochure, International Publication No. 2016 / 057846, released on April 14, 2016... It is an anti-GITR antibody molecule as described.

[0235] In one embodiment, the anti-GITR antibody molecule is one of those shown in Table 9 (for example, disclosed in Table 9). (From the heavy and light chain variable region sequences of MAB7, or the nucleotide sequences shown in Table 9) At least one of the heavy chain and light chain variable regions containing the amino acid sequence encoded by the column 1, 2, 3, 4, 5, or 6 complementarity determination regions (CDRs) (or all CDRs collectively) This includes. In some embodiments, the CDR is a Kabat definition (for example, as shown in Table 9). (as described) In some embodiments, CDR is defined by Chothia (e.g.) For example, as described in Table 9. In one embodiment, one or more CDRs (or all CDRs together) have 1, 2, 3, 4, 5, 6 or more variations, for example, in Table 9 The nucleotide sequence shown in or encoded in Table 9 It has amino acid substitutions (e.g., conservative amino acid substitutions) or deletions in the amino acid sequence.

[0236] In one embodiment, the anti-GITR antibody molecule is SEQ ID NO: 90, as disclosed in Table 9. The VHCDR1 amino acid sequence of sequence 9, the VHCDR2 amino acid sequence of sequence number 911, and sequence number The heavy chain variable region (VH) containing the VHCDR3 amino acid sequence of number 913, and SEQ ID NO: 91 The amino acid sequence of VLCDR1 of sequence 4, the amino acid sequence of VLCDR2 of sequence number 916, and sequence number It contains a light chain variable region (VL) including the VLCDR3 amino acid sequence of no. 918.

[0237] In one embodiment, the anti-GITR antibody molecule is the amino acid sequence of SEQ ID NO: 901 or the sequence Contains an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to number 901. It contains VH. In one embodiment, the anti-GITR antibody molecule is the amino acid of SEQ ID NO: 902 A symmetry that is at least 85%, 90%, 95%, or 99% identical to sequence or sequence number 902. It contains a VL containing a noacid sequence. In one embodiment, the anti-GITR antibody molecule is SEQ ID NO 90 It contains VH, which has the amino acid sequence of 1, and VL, which has the amino acid sequence of SEQ ID NO: 902.

[0238] In one embodiment, the antibody molecule is the nucleotide sequence of SEQ ID NO: 905 or SEQ ID NO: 9 By a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to 05 It contains VH, which is coded as follows: In one embodiment, the antibody molecule contains the nucleus of SEQ ID NO: 906. The Otid sequence or sequence number 906 is identical to at least 85%, 90%, 95%, or 99% or more of the Otid sequence. It contains a VL encoded by a nucleotide sequence. In one embodiment, the antibody molecule , VH encoded by the nucleotide sequence of SEQ ID NO: 905 and nucleotide sequence NO: 906 Includes VL encoded by a creotide sequence.

[0239] In one embodiment, the anti-GITR antibody molecule is the amino acid sequence of SEQ ID NO: 903 or the sequence Contains an amino acid sequence that is at least 85%, 90%, 95%, or 99% or more identical to number 903. It contains heavy chains. In one embodiment, the anti-GITR antibody molecule is the amino acid of SEQ ID NO: 904 A symmetry that is at least 85%, 90%, 95%, or 99% identical to sequence or sequence number 904. It contains a light chain that includes an acid sequence.

[0240] In one embodiment, the anti-GITR antibody molecule contains the amino acid sequence of SEQ ID NO: 903. It includes a chain and a heavy chain containing the amino acid sequence of SEQ ID NO: 904.

[0241] In one embodiment, the antibody molecule is the nucleotide sequence of SEQ ID NO: 907 or SEQ ID NO: 9 By a nucleotide sequence that is at least 85%, 90%, 95%, or 99% or more identical to 07 It contains a heavy chain encoded by . In one embodiment, the antibody molecule contains the nucleus of SEQ ID NO: 908 The Otid sequence or sequence number 908 is identical to at least 85%, 90%, 95%, or 99% or more of the Otid sequence. It contains a light chain encoded by a nucleotide sequence. In one embodiment, the antibody molecule , the heavy chain encoded by the nucleotide sequence of SEQ ID NO: 907 and the nucleotide sequence of SEQ ID NO: 908 It contains a light chain encoded by a creotide sequence.

[0242] The antibody molecules described herein are referred to collectively by International Publication No. 201. Prepared by the vector, host cells, and method described in pamphlet No. 6 / 057846. It is possible.

[0243] [Table 29]

[0244] [Table 30]

[0245] [Table 31]

[0246] In some embodiments, GITR agonists are administered in doses ranging from approximately 2 mg to approximately 600 mg (for example, It is administered in doses of approximately 5 mg to 500 mg. In some embodiments, GITR agon The agonist is administered once a week. In other embodiments, the GITR agonist is administered once a week. It is administered once a week. In another embodiment, the GITR agonist is administered once every six weeks. To be given.

[0247] In some embodiments, the GITR agonist is administered in doses of approximately 2 mg to approximately 10 mg (for example, approximately 5mg), approximately 5mg to approximately 20mg (for example, approximately 10mg), approximately 20mg to approximately 40mg (for example) For example, about 30 mg, about 50 mg to about 100 mg (for example, about 60 mg), about 100 mg ~200mg (for example, about 150mg), about 200mg~about 400mg (for example, about 3 Dosages of 00 mg or approximately 400 mg to approximately 600 mg (for example, approximately 500 mg) per week It is administered as a single dose.

[0248] In some embodiments, the GITR agonist is administered in doses of approximately 2 mg to approximately 10 mg (for example, approximately 5mg), approximately 5mg to approximately 20mg (for example, approximately 10mg), approximately 20mg to approximately 40mg (for example) For example, about 30 mg, about 50 mg to about 100 mg (for example, about 60 mg), about 100 mg ~200mg (for example, about 150mg), about 200mg~about 400mg (for example, about 3 Dosages of 00 mg or approximately 400 mg to approximately 600 mg (for example, approximately 500 mg) for 3 weeks It is administered as a single dose.

[0249] In some embodiments, the GITR agonist is administered in doses of approximately 2 mg to approximately 10 mg (for example, approximately 5mg), approximately 5mg to approximately 20mg (for example, approximately 10mg), approximately 20mg to approximately 40mg (for example) For example, about 30 mg, about 50 mg to about 100 mg (for example, about 60 mg), about 100 mg ~200mg (for example, about 150mg), about 200mg~about 400mg (for example, about 3 A dose of 00 mg or approximately 400 mg to approximately 600 mg (for example, approximately 500 mg) for 6 weeks It is administered as a single dose.

[0250] In some embodiments, three doses of the GITR agonist are administered over a period of three weeks. After that, there is a 9-week break. In some embodiments, four doses of the GITR agonist are The drug is administered over 12 weeks, followed by a 9-week break. In some embodiments, GITR The agonist is administered in four doses over 21 or 24 weeks, followed by a 9-week break.

[0251] Other exemplary GITR agonists In one embodiment, the anti-GITR antibody molecule is BMS 986156 or BMS986 BMS-986156 (Bristol-Myers Squi) bb) is. BMS-986156 and other anti-GITR antibodies, for example, as a whole, are used. U.S. Patent No. 9,228,016 and International Publication No. 2016 / 1 are referenced herein. This is disclosed in brochure No. 96792. In one embodiment, an anti-GITR antibody fraction For example, the child is one of the CDR sequences of BMS-986156 as disclosed in Table 10. The upper (or all CDR sequences collectively), heavy chain or light chain variable region sequences, or heavy chain or Includes light chain sequence.

[0252] In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Mer ck) is. MK-4166, MK-1248 and other anti-GITR antibodies are, for example, all U.S. Patent No. 8,709,424, International Publication No. 20, as incorporated by reference. Brochure No. 11 / 028683, International Publication No. 2015 / 026684 and Mahne et al. Cancer Res. 2017;77(5):1108 Disclosed in -1118. In one embodiment, the anti-GITR antibody molecule is MK-4166 Or one or more of the CDR sequences of MK-1248 (or all CDR sequences together), heavy chain Alternatively, it may include a light chain variable region sequence or a heavy chain or light chain sequence.

[0253] In one embodiment, the anti-GITR antibody molecule is TRX518 (Leap Therapy). (eutics) TRX518 and other anti-GITR antibodies, for example, as a whole, U.S. Patent No. 7,812,135 and U.S. Patent No. 8,388,9 are referenced herein. U.S. Patent No. 67, U.S. Patent No. 9,028,823, International Publication No. 2006 / 1050 Pamphlet No. 21 and Ponte J et al. (2010) Clinical Disclosed in Immunology;135:S96. In one embodiment, anti-GITR The antibody molecule contains one or more (or all) CDR sequences of TRX518. Includes a heavy chain or light chain variable region sequence or a heavy chain or light chain sequence.

[0254] In one embodiment, the anti-GITR antibody molecule is INCAGN1876(Incyte / Agenus) is. INCAGN1876 and other anti-GITR antibodies are, for example, whole U.S. Patent Application Publication No. 2015 / 0368349, as incorporated by reference, and Disclosed in International Publication No. 2015 / 184099. In one embodiment... Furthermore, the anti-GITR antibody molecule contains one or more (or a whole) CDR sequences of INCAGN1876. (including all CDR sequences), heavy chain or light chain variable region sequences, or heavy chain or light chain sequences nothing.

[0255] In one embodiment, the anti-GITR antibody molecule is AMG 228 (Amgen). AMG 228 and other anti-GITR antibodies are, for example, referenced by the United States as a whole. National Patent No. 9,464,139 Specification and International Publication No. 2015 / 031667 Pamphlet This is disclosed in the document. In one embodiment, the anti-GITR antibody molecule is AMG 228 One or more CDR sequences (or all CDR sequences collectively), heavy chain or light chain variable region Includes sequences or heavy chain or light chain sequences.

[0256] In one embodiment, the anti-GITR antibody molecule is INBRX-110(Inhibrx) INBRX-110 and other anti-GITR antibodies are, for example, by reference as a whole. The United States Patent Application Publication No. 2017 / 0022284 and International Publication No. 201 are cited. This is disclosed in brochure No. 7 / 015623. In one embodiment, GITR The gonist is one or more of the CDR sequences of INBRX-110 (or all of the CDR sequences at once). Includes a column, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence.

[0257] In one embodiment, the GITR agonist (e.g., fusion protein) is MEDI1 This is MEDI 1873 (MedImmune), also known as 873. 1873 and other GITR agonists, for example, are quoted by reference in the United States as a whole. Patent Application Publication No. 2017 / 0073386, International Publication No. 2017 / 025610 Pamphlet No. 1 and Ross et al. Cancer Res 2016;76(1 4 Suppl): Disclosed in Abstract nr 561. In one embodiment GITR agonists include the IgG Fc domain, the functional multimerization domain, and MEDI 1873 glucocorticoid-inducible TNF receptor ligand (GITRL) receptor Includes one or more combined domains.

[0258] In one embodiment, the anti-GITR antibody molecule is incorporated herein by reference as a whole. Anti-GITR antibody molecules disclosed in International Publication No. 2013 / 039954 In one embodiment, the anti-GITR antibody molecule is described herein by reference as a whole. Anti-GIT disclosed in U.S. Patent Application Publication No. 2014 / 0072566, which is referenced This is an R antibody molecule.

[0259] Further known GITR agonists (e.g., anti-GITR antibodies) include, for example, the whole As referenced by International Publication No. 2016 / 054638 Some examples include:

[0260] In one embodiment, the anti-GITR antibody is one of the anti-GITR antibodies described herein. Antibodies that compete for and / or bind to the same epitope on GITR be.

[0261] In one embodiment, a GITR agonist activates the GITR signaling pathway. It is a peptide. In one embodiment, the GITR agonist has a constant region (e.g., immune An immunoadhesin-binding fragment (e.g., GITRL) fused to the Fc region of a globulin sequence. It is an immunoadhesin-binding fragment containing the extracellular portion or GITR-binding portion.

[0262] [Table 32]

[0263] TGF-β inhibitors In a particular embodiment, the combination described herein transforms Growth factor beta (as used synonymously in this specification, TGF-β, TGFβ, TGFb, or T) Includes inhibitors (also known as GF-beta).

[0264] TGF-β is, for example, a bone morphogenetic protein (BMP), a growth and differentiation factor, and an activin. It belongs to a large family of structurally related cytokines, including inhibin. In the embodiments described herein, the TGF-β inhibitors are one or more TGF-β molecules. isoforms (e.g., one or two of TGF-β1, TGF-β2, or TGF-β3) It can bind to (or all of) and / or inhibit them.

[0265] Under normal conditions, TGF-β maintains homeostasis and, for example, provides antiproliferative and apoptotic properties. It restricts the proliferation of epithelial cells, endothelial cells, nerve cells, and hematopoietic cell lineages by inducing a response. Classical and non-classical signaling pathways are involved in the cellular response to TGF-β. Activation of the classical β / Smad pathway can mediate the antiproliferative effect of TGF-β. Non-classical T The GF-β pathway is an additional intracellular pathway, such as mitogen-activated protein kinase (M APK) Phosphatidylinositol 3-kinase / protein kinase B, Rho-like G TP-ase can be activated (Tian et al. Cell Signal. 2011; 23(6):951-62;Blobe et al.N Engl J Med.20 00;342(18):1350-8), thereby epithelial-mesenchymal transition (EMT) and / or It regulates cell motility.

[0266] Modification of the TGF-β signaling pathway is associated with human diseases such as cancer, cardiovascular disease, fibrosis, and biology. It is associated with reproductive disorders and wound healing. Although not bound by theory, in some embodiments... Furthermore, the role of TGF-β in cancer is related to the disease status (e.g., tumor stage and gene mutations). ) and / or it is thought to depend on the cellular status. For example, in the later stages of cancer, T GF-β may, for example, promote tumor growth (e.g., induce EMT) or have an antitumor response. By blocking cancer-related fibrosis, increasing tumor-associated fibrosis, or promoting angiogenesis, cancer-related The process can be adjusted (Wakefield and Hill National Rev C ancer.2013;13(5):328-41). In certain embodiments, this specification Using combinations of TGF-β inhibitors described in the book, late-stage cancer and metastases can be treated. Treating cancerous or advanced cancer.

[0267] Preclinical evidence indicates that TGF-β plays an important role in immune regulation. Wojtowicz-Praga Invest New Drugs.2003;21 (1):21-32;Yang et al.Trends Immunol.2010 ;31(6):220-7). TGF-β suppresses the host immune response through several mechanisms. Controllable transitions, for example, the shift in T helper balance toward the Th2 immunophenotype; antitumor Th Inhibition of type 1 response and M1 macrophages; cytotoxic CD8+ T lymphocytes (CTLs), Suppression of NK lymphocyte and dendritic cell function, generation of CD4+CD25+ regulatory T cells; or immunity Epidemiological suppressive cytokines (e.g., IL-10 or VEGF), pro-inflammatory cytokines (e.g.) For example, M2 (which has tumor-promoting activity mediated by the secretion of IL6, TNFα, or IL1) Promotes type macrophages and generates reactive oxygen species (ROS) with genotoxic activity (Yan g et al.Trends Immunol.2010;31(6):220-7; Truty and Urrutia Pancreatology.2007;7(5 -6):423-35;Achyut et al Gastroenterolog y.2011;141(4):1167-78).

[0268] In some embodiments, the TGF-β inhibitor is a PD-1 inhibitor and a LAG-3 inhibitor. , GITR agonists, c-MET inhibitors, IDO inhibitors or A2aR antagonists Used in combination with one or more (e.g., two, three, four, or all). Some embodiments In this context, a combination is used to treat pancreatic cancer, colorectal cancer, gastric cancer, or melanoma (for example, refractory cancer). To treat melanoma. In some embodiments, the TGF-β inhibitor is fresolimmab. Alternatively, it can be selected from XOMA 089.

[0269] Imaginary TGF-β inhibitors In some embodiments, the TGF-β inhibitor is referred to as XOMA 089 or as a whole. Disclosed in the brochure for International Publication No. 2012 / 167143, which is referenced by the International Patent Application Publication. It contains compounds that are included.

[0270] XOMA 089 is also known as XPA.42.089. XOMA 089 is, A fully human monoclonal compound that specifically binds to and neutralizes TGF-beta 1 and 2 ligands. It is an antibody.

[0271] The heavy chain variable region of XOMA 089 is [ka] (Disclosed as Sequence ID No. 6 in International Publication No. 2012 / 167143) It has an amino acid sequence. The light chain variable region of XOMA 089 is [ka] (Disclosed as Sequence ID No. 8 in International Publication No. 2012 / 167143) It has an amino acid sequence.

[0272] XOMA 089 binds to human TGF-β isoforms with high affinity. In general, XOMA 089 has a high affinity for TGF-β1 and TGF-β2. Furthermore, it binds to TGF-β3 to a smaller degree. Biacore assay In this study, the K of XOMA 089 against human TGF-β D Regarding TGF-β1, 1 4.6 pM, 67.3 pM for TGF-β2, and 948 pM for TGF-β3. Yes. Assuming high affinity binding to all three TGF-β isoforms, In a specific embodiment, XOMA 089 is XOMA as described herein. XOMA 089 is expected to bind to TGF-β1, β2, and β3 at dose 089. It cross-reacts with rodent and cynomolgus monkey TGF-β and exhibits functional activity in vitro and in vivo. This will be used to create rodents and cynomolgus macaque-related species for toxicity testing.

[0273] While not bound by theory, in some embodiments, PD-1 immunotherapy Resistance to this includes, for example, TGF-β signaling and TGF-β-dependent processes, for example, creation It is thought to be associated with the presence of transcriptional signatures containing genes related to wound healing or angiogenesis. (Hugo et al. Cell. 2016;165(1):35-44). In this embodiment, the TGF-β blocker is used in the treatment of therapies that inhibit the PD-1 / PD-L1 system. Expanding the therapeutic scope. TGF-β inhibitors are used, for example, in the tumor microenvironment, such as angiogenesis and fibrosis. Alternatively, by regulating factors that affect the recruitment of effector T cells, PD-1 immunity can be improved. This may affect the clinical usefulness of the therapy (Yang et al. Trends Imm). unol.2010;31(6):220-7;Wakefield and Hill Nat Rev Cancer.2013;13(5):328-41;Truty and Urrutia Pancreatology.2007;7(5-6):42 3-35).

[0274] Although not bound by theory, in some embodiments, the antitumor immune cycle Several elements express both PD-1 and TGF-β receptors, and PD-1 and TGF- It is also thought that β-receptors may increase non-redundant cellular signaling. For example, In a mouse model of prostate cancer, the functionally inhibited form of TGFBRII or in T cells The use of any of the methods to suppress TGF-β production slows tumor growth (Donkor et al. al.Immunity.2011;35(1):123-34;Diener et al. al. Lab Invest. 2009;89(2):142-51). Mouse prostate ( Studies in TRAMP mice with transgenic adenocarcinomas have shown that adoptive transition T cells Blocking TGF-β signaling has been shown to increase their persistence and antitumor activity. (Chou et al.J Immunol.2012;189(8):3936- 46). The antitumor activity of migrated T cells contributes to the upregulation of PD-1 in tumor-infiltrating lymphocytes. It may be partially reduced over time, but this is due to PD- as described herein. Supports the combination of 1 and TGF-β inhibition. The use of neutralizing antibodies also addresses the high expression levels of PD-1 and TGF-β stimulation. Assuming their responsiveness, it is possible to influence Treg (Riella et al. al.Am J Transplant.2012;12(10):2575-87) For example, by enhancing the regulation of Treg differentiation and function, PD- I support the combination of 1 and TGF-β inhibition.

[0275] While not bound by theory, cancer uses TGF-β to promote tumor growth and metastasis. It is thought that immune surveillance can be evaded in order to promote the growth. For example, in certain advanced cancers High levels of TGF-β are associated with tumor aggressiveness and a poor prognosis, and TGF-β levels are linked to tumor activity. The pathway can promote one or more of the cancer cell motility, invasion, EMT, or hepatocyte phenotype. Immune regulation mediated by leukocyte populations (for example, molecules expressed or secreted by various cells) For example, mediated by IL-10 or TGF-β) as monotherapy in certain patients The response to checkpoint inhibitors can be limited. In certain embodiments, check A combination of a point inhibitor (e.g., a PD-1 inhibitor as described herein) and TGF-β Using combined inhibitors, checkpoint inhibitor (e.g., anti-PD-1) monotherapy Cancers that do not respond or respond poorly to treatment, such as pancreatic cancer or colorectal cancer (e.g., mic To treat Rosatellite-stable colorectal cancer (MSS-CRC). In other embodiments, , checkpoint inhibitors (e.g., PD-1 inhibitors as described herein) and TGF Using inhibition in combination with -β, cancers showing high levels of effector T cell infiltration, For example, lung cancer (e.g., non-small cell lung cancer), breast cancer (e.g., 3-negative breast cancer), liver cancer (e.g., Treats hepatocellular carcinoma, prostate cancer, or kidney cancer (e.g., clear cell renal cell carcinoma). Partial implementation Morphologically, the combination of TGF-β inhibitors and PD-1 inhibition produces a synergistic effect. vinegar.

[0276] In one embodiment, the TGF-β inhibitor (e.g., XOMA 089) is 0.1 mg / kg~20mg / kg, for example 0.1mg / kg~15mg / kg, 0.1mg / kg ~12mg / kg, 0.3mg / kg~6mg / kg, 1mg / kg~3mg / kg, 0 .1mg / kg~1mg / kg, 0.1mg / kg~0.5mg / kg, 0.1mg / k g~0.3mg / kg, 0.3mg / kg~3mg / kg, 0.3mg / kg~1mg / Doses of 3 mg / kg to 6 mg / kg or 6 mg / kg to 12 mg / kg, for example, approximately 0.1mg / kg, 0.3mg / kg, 0.5mg / kg, 1mg / kg, 3mg / kg For example, once a week for two weeks, at doses of 6 mg / kg, 12 mg / kg, or 15 mg / kg. It is administered once in between, once every three weeks, once every four weeks, or once every six weeks.

[0277] In one embodiment, the TGF-β inhibitor (e.g., XOMA 089) is 0.1 mg / kg~15mg / kg (for example, 0.3mg / kg~12mg / kg or 1mg / kg) ~6 mg, for example, approximately 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg Administered, for example, once every three weeks, at doses of 6 mg / kg, 12 mg / kg, or 15 mg / kg. For example, a TGF-β inhibitor (e.g., XOMA 089) is administered at a dose of 0.1 mg / kg. ~1 mg / kg (for example, 0.1 mg / kg to 1 mg / kg, for example, 0.3 mg / kg) It may be administered, for example, once every three weeks, at a dose of . In one embodiment, a TGF-β inhibitor (e.g. For example, XOMA 089 is administered intravenously.

[0278] In some embodiments, the TGF-β inhibitor is a PD-1 inhibitor (e.g., anti-PD-1 inhibitor). It is administered in combination with an antibody molecule.

[0279] In one embodiment, the TGF-β inhibitor (e.g., XOMA 089) is 0.1 mg / kg~15mg / kg (for example, 0.3mg / kg~12mg / kg or 1mg / kg) ~6 mg, for example, approximately 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg For example, once every three weeks, in doses of 6 mg / kg, 12 mg / kg, or 15 mg / kg. For example, it is administered intravenously, and PD-1 inhibitors (e.g., anti-PD-1 antibody molecules) are administered within 50 minutes. g~500mg (for example, 100mg~400mg, for example, approximately 100mg, 200mg, For example, once every three weeks or once every four weeks, in doses of 300 mg or 400 mg. For example, it is administered by intravenous infusion. In some embodiments, a PD-1 inhibitor (e.g.) The anti-PD-1 antibody molecule is administered in doses of 100 mg to 300 mg (for example, about 100 mg, 2 Administer in doses of 00 mg or 300 mg, for example, once every three weeks, for example, by intravenous infusion. It will be done.

[0280] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is present at approximately 0. For example, once every three weeks, administered by intravenous infusion at a dose of 1 mg / kg or 0.3 mg / kg. It is administered as follows, and PD-1 inhibitors (e.g., anti-PD-1 antibody molecules) are given in doses of approximately 100 mg. The dosage is administered, for example, once every three weeks, for example, by intravenous infusion. In some embodiments In contrast, TGF-β inhibitors (e.g., XOMA 089) are administered at a dose of approximately 0.3 mg / kg. For example, administered once every three weeks, for example by intravenous infusion, and containing a PD-1 inhibitor (e.g., The anti-PD-1 antibody molecule is administered in doses of approximately 100 mg or 300 mg, for example, once every three weeks. For example, it is administered by intravenous infusion. In some embodiments, TGF-β inhibitors (e.g.) For example, XOMA 089 is available in doses of approximately 1 mg / kg, 3 mg / kg, 6 mg / kg, and 12 mg. Administer at a dose of 15 mg / kg or 15 mg / kg, for example, once every three weeks, for example, by intravenous infusion. Furthermore, PD-1 inhibitors (e.g., anti-PD-1 antibody molecules) are administered at a dose of approximately 300 mg. For example, it is administered once every three weeks, for instance, by intravenous infusion.

[0281] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is 0.1 A dose of mg to 0.2 mg (for example, about 0.1 mg / kg) is administered, for example, once every three weeks, for example Administered by intravenous infusion, and containing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), A dose of 50mg to 200mg (for example, about 100mg) is administered, for example, once every three weeks, for example, intravenously. It is administered by intravenous infusion.

[0282] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is 0.2 A dose of 0.5 mg (for example, about 0.3 mg / kg) is administered, for example, once every 3 weeks, for example Administered by intravenous infusion, and containing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), A dose of 50mg to 200mg (for example, about 100mg) is administered, for example, once every three weeks, for example, intravenously. It is administered by intravenous infusion.

[0283] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is 0.2 A dose of 0.5 mg (for example, about 0.3 mg / kg) is administered, for example, once every 3 weeks, for example Administered by intravenous infusion, and containing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), 200mg to 400mg (for example, about 300mg) administered intravenously, for example, once every three weeks. It is administered by injection.

[0284] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is 0.5 A dose of 1 mg to 2 mg (for example, approximately 1 mg / kg) administered intravenously, for example, once every 3 weeks. Administered via injection, and PD-1 inhibitors (e.g., anti-PD-1 antibody molecules) are administered in 200 ml doses. g-400mg (for example, about 300mg) is administered, for example, once every three weeks, for example, by intravenous infusion. It is administered as such.

[0285] In some embodiments, the TGF-β inhibitor (e.g., XOMA 089) is 2 mg A dose of ~5 mg (for example, approximately 3 mg / kg) administered, for example, once every three weeks, for example, by intravenous infusion. Therefore, the PD-1 inhibitor (e.g., anti-PD-1 antibody molecule) is administered at a dose of 200 mg or more. 400 mg (for example, about 300 mg) is administered, for example, once every three weeks, by intravenous infusion. It will be administered.

[0286] In some embodiments, the TGF-β inhibitor (e.g., XOMA 089) is 5 mg A dose of ~10 mg (for example, approximately 6 mg / kg) administered, for example, once every three weeks, for example, by intravenous infusion. The drug is administered by [method / organization], and the PD-1 inhibitor (e.g., anti-PD-1 antibody molecule) is 200 mg. ~400mg (for example, about 300mg) is administered, for example, once every three weeks, for example, by intravenous infusion. It is administered.

[0287] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is used in 10m A dose of 15 mg (for example, about 12 mg / kg) administered intravenously, for example, once every three weeks. Administered by infusion, and containing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), 200 400 mg (for example, about 300 mg) administered intravenously, for example, once every three weeks. Therefore, it is administered.

[0288] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is used in 10m A dose of 20 mg (for example, about 15 mg / kg) administered intravenously, for example, once every three weeks. Administered by infusion, and containing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules), 200 400 mg (for example, about 300 mg) administered intravenously, for example, once every three weeks. Therefore, it is administered.

[0289] In some embodiments, a TGF-β inhibitor (e.g., XOMA 089) is used in PD- 1. It is administered before the administration of the inhibitor (e.g., an anti-PD-1 antibody molecule). In other embodiments... In this context, TGF-β inhibitors (e.g., XOMA 089) are used as PD-1 inhibitors (e.g., It is administered after the administration of an anti-PD-1 antibody molecule. In certain embodiments, TGF- β inhibitors (e.g., XOMA 089) and PD-1 inhibitors (e.g., anti-PD-1 antibody) The child should allow at least 30 minutes (e.g., at least 1, 1.5, or 2 hours) between the two doses. They are administered separately, with interruptions between doses.

[0290] In some embodiments, the combination is a PD-1 inhibitor (for example, as described herein). PD-1 inhibitors (e.g., TGF-β inhibitors as described herein) Harmful agents) and MEK inhibitors (e.g., MEK inhibitors as described herein), IL-1β inhibitors Harmful agents (e.g., IL-1b inhibitors as described herein) or A2aR antagonists ( For example, including one or more A2aR antagonists described herein. (Theoretical constraints) Although not generally the case, in some embodiments, TGFβ is found in CRC and pancreatic cancer. It promotes immunosuppression by a Treg subset. In some embodiments, PD-1 inhibitor Harmful agents, TGF-β inhibitors and MEK inhibitors, IL-1b inhibitors or A2aR antagonists A combination containing one or more of the following is, for example, a therapeutically effective dose for a subject with CRC or pancreatic cancer. It is administered as follows.

[0291] In some embodiments, PD-1 inhibitors (e.g., PD-1 inhibitors described herein) are used. A harmful agent) and a TGF-β inhibitor (e.g., a TGF-β inhibitor as described herein) The combination, compared to either single agent alone, in the mouse MC38 CRC model... It shows improved efficacy in controlling tumor growth. Although not bound by theory, some In this embodiment, the TGF-β inhibitor combined with the PD-1 inhibitor is the PD-1 inhibitor It is thought that this improves, for example, the effectiveness of C PD-1 inhibitors administered to subjects having RC (e.g., PD-1 as described herein) Includes inhibitors and TGF-β inhibitors (for example, TGF-β inhibitors as described herein). Certain combinations may lead to improved, for example, increased, efficacy of PD-1 inhibitors.

[0292] Other exemplary TGF-β inhibitors In some embodiments, the TGF-β inhibitor is fresolimmab (CAS Registry No. 9 Includes 48564-73-6). Fresolimumab is also known as GC1008. Lesolimumab binds to and inhibits TGF-beta isoforms 1, 2, and 3 in humans. It is a monoclonal antibody.

[0293] The heavy chain of fresolimmab is [ka] It has the following amino acid sequence.

[0294] The light chain of fresolimmab is [ka] It has the following amino acid sequence.

[0295] Fresolimub is referenced by reference as a whole, for example, in the International Publication No. Brochure No. 2006 / 086469 and U.S. Patent No. 8,383,780 and This is disclosed in Patent No. 8,591,901.

[0296] IL-15 / IL-15Ra complex In certain embodiments, the combinations described herein are IL-15 / IL-1 Includes a 5Ra complex. In some embodiments, the IL-15 / IL-15Ra complex is NIZ985 (Novartis), ATL-803 (Altor), or CYP0150 Selected from (Cytune). In some embodiments, IL-15 / IL-15R Complex A is NIZ985. Although not bound by theory, in some embodiments... In this context, IL-15 strengthens natural killer cells, for example, enhancing them and inhibiting pancreatic cancer cells. It is thought that they are removed, for example, killed. In one embodiment, for example, colorectal cancer The combinations described herein in animal models, for example, IL-15 / IL15R Responses to combinations containing the α complex, such as therapeutic responses, include natural killer cell infiltration. It is related to this.

[0297] Exemplary IL-15 / IL-15Ra complex In one embodiment, the IL-15 / IL-15Ra complex is a mobile form of human IL-15Ra. Contains human IL-15 that has formed a complex with a soluble form. The complex contains soluble IL-15Ra. The morphology may include IL-15 bonded covalently or noncovalently. Specific embodiments In this process, human IL-15 is noncovalently bound to the soluble form of IL-15Ra. In certain embodiments, the human IL-15 of the composition is the same as Sequence ID No. 100 in Table 11. Containing the amino acid sequence of 1, the soluble form of human IL-15Ra is supported by reference as a whole. Table 11 as described in the International Publication No. 2014 / 066527 used The amino acid sequence of SEQ ID NO: 1002 is included in the above. The molecules described herein are whole and As referenced by the International Publication No. 2007 / 084342, It can be produced by vectors, host cells, and methods.

[0298] [Table 33]

[0299] While not bound by theory, microsatellite stability C with low T cell infiltration In RC, IL-15 is thought to promote, for example, increase T cell priming. (For example, Lou,KJSciBX 7(16);10.1038 / SCIB) (As described in X.2014.449). In some embodiments, the combination This includes PD-1 inhibitors (e.g., PD-1 inhibitors as described herein), IL-15 / IL15RA complex (e.g., the IL-15 / IL15RA complex described herein) and MEK inhibitors (e.g., MEK inhibitors as described herein), IL-1b inhibitors ( For example, IL-1b inhibitors as described herein or A2aR antagonists (for example) , comprising one or more A2aR antagonists described herein. In this context, the combination promotes, for example, T cell priming, increasing it. (Theory constraints) Although not directly related, it is further thought that IL-15 may induce NK cell infiltration. In this embodiment, a PD-1 inhibitor, an IL-15 / IL-15RA complex, and a MEK inhibitor are used. Responses to one or more harmful agents, IL-1b inhibitors, or A2Ar antagonists are detected by NK cells. This can lead to cystic infiltration.

[0300] Other exemplary IL-15 / IL-15Ra complexes In one embodiment, the IL-15 / IL-15Ra composite is ALT-803, IL- 15 / IL-15Ra Fc fusion protein (IL-15N72D:IL-15RaSu (Fc-soluble complex). ALT-803 is incorporated herein by reference as a whole. Disclosed in International Publication No. 2008 / 143794, in one embodiment The IL-15 / IL-15Ra Fc fusion protein is disclosed in Table 12. Includes an array of.

[0301] In one embodiment, the IL-15 / IL-15Ra composite is IL-15Ra(CYP Contains IL-15 fused to the sushi domain of 0150 (Cytune). The sushi domain of 15Ra is the first sushi after the signal peptide of IL-15Ra. A cysteine ​​residue that begins with a cysteine ​​residue and ends with the fourth cysteine ​​residue after the signal peptide. This refers to the main. The IL-15 complex fused to the sushi domain of IL-15Ra is , and the International Publication No. 2007 / 04606, which is referenced in whole. Disclosed in International Publication No. 2012 / 175222. In one embodiment, IL -15 / IL-15Ra sushi domain fusion is distributed as disclosed in Table 12. Includes columns.

[0302] [Table 34]

[0303] PRRT agent In relation to the present invention, the PRRT agent is a finely linked radionuclide 177Lu and a chelating agent. It is a complex formed by the receptor-binding site.

[0304] The cell receptor binding portion and the chelating agent can be formed by combining the following molecules. DOTA-OC:[DOTA 0 ,D-Phe 1 Octreotide, DOTA-TOC is represented by the following formula:[DOTA 0 ,D-Phe 1 ,Tyr 3 ] Octreotide, Edtreotide (INN): [ka] DOTA-NOC:[DOTA 0 ,D-Phe 1 ,1-Nal 3 Octreotide, DOTA-TATE is represented by the following formula:[DOTA 0 ,D-Phe 1 ,Tyr 3 Octreotete, DOTA-Tyr 3 -Octoleotete, DOTA-d-Phe- Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr (Cyclo 2,7), Oxy Sodotreotide (INN): [ka] DOTA-LAN:[DOTA 0 ,D-β-Nal 1 ] Ranleotide, DOTA-VAP:[DOTA 0, D-Phe 1 , Tyr 3 Bapreotide. Satireotide trizoxetan [Chem.] Satireotide tetraxetan [Chem.]

[0305] Preferred "cell receptor binding moiety linked to a chelating agent" molecules for the present invention are DO TA-TOC, DOTA-TATE and satireotide tetraxetan, and more preferably the molecule is DOTA-TATE.

[0306] Regarding the present invention, a preferred complex (or its preferred complex) formed by the radionuclide according to the present invention and the cell receptor binding moiety linked to a chelating agent is 177 -Lu-DO TA-TATE, which is lutetium (177Lu) oxodotreotide (INN ), that is, hydrogen [N-{[4,7,10-tris(carboxylato-κO-methyl)-1, 4,7,10-tetraazacyclododecan-1-yl-κ 4 N 1 ,N 4 ,N 7 ,N 10 acetyl-κO}-D-phenylalanyl-L-cysteinyl-tyrosyl-D-trypto phil-L-lysyl-L-threonyl-L-cysteinyl-L-threoninato cyclic (2→ 7)-disulfide(4-)](177Lu) lutetate(1-), and is also referred to as the following and is represented by the formula: [Chem.] ​

[0307] Further anticancer drugs This invention relates to radionuclides 177 Lu (Lutetium-177) and as defined herein A complex formed by somatostatin receptor-binding peptide linked to a chelating agent. A combination of therapies or combination therapy or one of the further therapeutic agents outlined below. A combination or combination of pharmaceutical aqueous solutions as defined herein. To provide further treatment.

[0308] In certain cases, the pharmaceutical aqueous solution of the present invention may be used with other anticancer agents, anti-allergic agents, anti-nausea agents (or other anti-inflammatory drugs). Combined with other therapeutic agents such as emetics, pain relievers, cytoprotective agents, and combinations thereof. It can be done.

[0309] Common chemotherapeutic agents considered for use in combination therapy include Anas Trozole (Arimidex®), Bicalutamide (Casodex®) (Mark), Bleomycin sulfate (Blenoxane®), Busulfan (My Leran (registered trademark), Busulfex (registered trademark), Pecitabine (Xeloda®), N4-Pentoxycarbonyl-5-deoxy -5-fluorocytidine, carboplatin (Paraplatin®), car Mustine (BiCNU®), Chlorambucil (Leukeran®) ), cisplatin (Platinol®), cladribine (Leustati n(registered trademark), cyclophosphamide (Cytoxan(registered trademark) or Neosar (Registered Trademark)), Cytarabine, Cytosine Arabinoside (Cytosar-U (Registered Trademark) ), Cytarabine Liposome Injection (DepoCyt®), Dacarbazine (DT IC-Dome (registered trademark), Dactinomycin (Actinomycin D, Co) smegan), daunorubicin hydrochloride (Cerubidine®), citric acid Daunorubicin liposome injection (DaunoXome®), dexamethasone , docetaxel (Taxotere®), doxorubicin hydrochloride (Adriam Ycin (registered trademark), Rubex (registered trademark), etoposide (Vepesid (registered trademark)) (Trademark), Fludarabine phosphate (Fludara® registered trademark), 5-Fluorouracil (Adrucil (registered trademark), Efudex (registered trademark)), Flutamide (Eulex) in(registered trademark), tesacitibine, gemcitabine (difluorodeoxycytidine), hi Hydrea (registered trademark), Idamycin (registered trademark) Trademark), Ifosfamide (IFEX (registered trademark)), Irinotecan (Camptosa r(registered trademark), L-asparaginase (ELSPAR(registered trademark)), leucovorin Calcium, melphalan (Alkeran®), 6-mercaptopurine (P unethol (registered trademark), methotrexate (Folex (registered trademark)), mi Toxantrone (Novantrone®), Mylotarg, Paclitaxel (Taxol(registered trademark)), nab-paclitaxel (Abraxane(registered trademark)) ), Phoenix (Yttrium 90 / MX-DTPA), Pentostatin, Calmusti Polyfeprosan 20 (Gliadel®), containing implants, citric acid Tamoxifen (Nolvadex®), Teniposide (Vumon®) )), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), Topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velb an(registered trademark), vincristine (Oncovin(registered trademark)), and vinorelbine (Navelbine(registered trademark)) is one example.

[0310] As anticancer agents of particular interest for combination with the pharmaceutical aqueous solution of the present invention, The following are examples:

[0311] Tyrosine kinase inhibitors: Erlotinib hydrochloride (Tarceva®); Lin Fanib (also known as ABT 869, available from Genentech) N-[4 -(3-amino-1H-indazole-4-yl)phenyl]-N'-(2-fluoro- 5-methylphenyl urea); sunitinib malate (Sutent®); Boss Tinib (also known as SKI-606, listed in U.S. Patent No. 6,780,996) (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy- 7-[3-(4-methylpiperazine-1-yl)propoxy]quinoline-3-carbonite Lil); Dasatinib (Sprycel(registered trademark)); Pazopanib (Votrient( (Registered Trademark)); Sorafenib (Nexavar (Registered Trademark)); Zactima (ZD6 474); and imatinib or imatinib mesylate (Gilvec® and Gl eevec(registered trademark).

[0312] Vascular endothelial growth factor (VEGF) receptor inhibitor: Bevacizumab (Avastin (Registered Trademark) Axitinib (Inlyta®); Brivanib alaninate (BMS) -582664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H- Ndol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazi (6-yloxy)propan-2-yl)2-aminopropanoate); sorafenib (Nexavar(registered trademark)); Pazopanib (Votrient(registered trademark)); Suni Tinib malate (Sutent®); Sediranib (AZD2171, CA) S 288383-20-1); Bargatev (BIBF1120, CAS 928326) -83-4); Foretinib (GSK1363089); Teratinib (BAY57-93 52. CAS 332012-40-5; Apatinib (YN968D1, CAS 811 803-05-1); Imatinib (Gleevec®); Ponatinib (AP2 4534, CAS 943319-70-8); tivozanib (AV951, CAS 47 5108-18-0); Regolafenib (BAY73-4506, CAS 755037) -03-7); Batalanib dihydrochloride (PTK787, CAS 212141-51-0) ;Brivanib (BMS-540215, CAS 649735-46-6); Bandetani (Caprelsa (registered trademark) or AZD6474); Motesanib diphosphate (AM G706, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethicone) (Lu-1H-indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinylmethyl Lysine carboxamide, PCT Publication Number International Publication No. 02 / 066470, in the pamphlet. (As described); Dovitinib dilactic acid (TKI258, CAS 852433-84-2) ); Linfarib (ABT869, CAS 796967-16-3); Cabozantinib (XL184, CAS 849217-68-1); Restaurtinib (CAS 111 358-88-4), N-[5-[[[5-(1,1-dimethylethyl)-2-oxazo [Lyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS38 703, CAS 345627-80-7); (3R,4R)-4-amino-1-((4 -((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazine -5-yl)methyl)piperidine-3-ol (BMS690514), N-(3,4- Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα) -Octahydro-2-methylcyclopenta[c]pyrrole-5-yl]methoxy]-4- Quinazolinamine (XL647, CAS 781613-23-8); 4-methyl-3- [[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidine- 4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide(B HG712, CAS 940310-85-0); and Aflibercept (Eylea( Registered trademark), sulfatinib, sulfatinib.

[0313] Platelet-derived growth factor (PDGF) receptor inhibitor: Imatinib (Gleevec (Registered Trademark) (Standard) ); Linifunib (also known as ABT 869, available from Genentech) N-[4-(3-amino-1H-indazole-4-yl)phenyl]-N'-(2 -Fluoro-5-methylphenyl)urea); sunitinib malate (Sutent (Registered Trademark) (Standard)); Quizartinib (AC220, CAS 950769-58-1); Pazopanib ( Votrient (registered trademark); Axitinib (Inlyta (registered trademark)); Solaf Enib (Nexavar®); Bargatev (BIBF1120, CAS 92) 8326-83-4); Teratinib (BAY57-9352, CAS 332012-4) 0-5); Batalanib dihydrochloride (PTK787, CAS 212141-51-0); and Motesanib diphosphate (AMG706, CAS 857876-30-3, N-(2, 3-Dihydro-3,3-dimethyl-1H-indole-6-yl)-2-[(4-pyridyl [Nylmethyl)amino]-3-pyridinecarboxamide, PCT Publication Number International Publication No. 02 / (As stated in pamphlet number 066470).

[0314] Fibroblast growth factor receptor (FGFR) inhibitor: Brivanib alaninate (BMS-5) 82664, (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indo (Il-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yloxy)propan-2-yl)2-aminopropanoate); bargatef (BI BF1120, CAS 928326-83-4); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); 3-(2,6-dichloro-3,5-dimethoxy-f Phenyl)-1-{6-[4-(4-ethyl-piperazine-1-yl)-phenylamino] -Pyrimidine-4-yl}-1-methylurea (BGJ398, CAS 872511- 34-7); danucertib (PHA-739358); and N-[2-[[4-(diethi [2,3-(3,5-dimethoxyphenyl)pyrido[2,3-d Pyrimidine-7-yl]-N'-(1,1-dimethylethyl)-urea (PD17307 4. CAS 219580-11-7). Sulfatinib.

[0315] Aurora kinase inhibitor: danucertib (PHA-739358); N-[4-[[6 -Methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinazolinyl]amino ]phenyl]benzamide (ZM447439, CAS 331771-20-1); 4 -(2-amino-4-methyl-5-thiazolyl)-N-[4-(4-morpholinyl)phen [Nyl]-2-pyrimidineamine (CYC116, CAS 693228-63-6); Zasertib (VX680 or MK-0457, CAS 639089-54-6); Ali Celtic (MLN8237); (N-{2-[6-(4-cyclobutylamino-5-tri Fluoromethyl-pyrimidine-2-ylamino)-(1S,4R)-1,2,3,4-Te [Trahydro-1,4-epiazano-naphthalene-9-yl]-2-oxo-ethyl}- Cetoamide) (PF-03814735), 4-[[9-chloro-7-(2,6-diflu Olophenyl)-5H-pyrimide[5,4-d][2]benzoazepine-2-yl]amine [N]-benzoic acid (MLN8054, CAS 869363-13-3); senicertib ( R-763); balasatib (AZD1152); and N-cyclopropyl-N'-[3- [6-(4-morpholinylmethyl)-1H-benzimidazole-2-yl]-1H-p Razole-4-yl]-urea (AT9283).

[0316] Cyclin-dependent kinase (CDK) inhibitors: Aloysin A; Arbocidib (Flavopin 2-(2-chlorophenyl)-5,7, also known as Lidol or HMR-1275 -Dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidine (As described in U.S. Patent No. 5,621,002) Crizotinib (PF-02341066, CAS 877399-52-5); 2-( 2-Chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxy [Cymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one, salt Salt (P276-00, CAS 920113-03-7); Indisram (E707) 0); Roscovitine (CYC202); 6-Acetyl-8-Cyclopentyl-5-methyl -2-(5-piperazine-1-ylpyridine-2-ylamino)-8H-pyrido[2, 3-d] Pyrimidine-7-one, hydrochloride (PD0332991); Dinaciclib (SC H727965);N-[5-[[(5-tert-butyloxazole-2-yl) [Chill]thio]thiazole-2-yl]piperidine-4-carboxamide (BMS 387 032, CAS 345627-80-7); 4-[[9-chloro-7-(2,6-diph Luolophenyl)-5H-pyrimide[5,4-d][2]benzoazepine-2-yl] Mino-benzoic acid (MLN8054, CAS 869363-13-3); 5-[3-( 4,6-difluoro-1H-benzoimidazole-2-yl)-1H-indazole-5 -yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS 837364-57-5); 4-(2,6-dichlorobenzoylamino)-1H -Pyrazole-3-carboxylic acid N-(piperidine-4-yl)amide (AT7519, C AS 844442-38-2); 4-[2-methyl-1-(1-methylethyl)-1H [-Imidazole-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrim Zinamine (AZD5438, CAS 602306-29-6); palbociclib (P D-0332991); and (2R,3R)-3-[[2-[[3-[[S(R)]-S -Cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethicone) (L)-4-pyrimidinyl[oxy]-2-butanol (BAY 10000394), Li Bosiclib.

[0317] Checkpoint kinase (CHK) inhibitors: 7-hydroxystaurosporine (UC N-01); 6-bromo-3-(1-methyl-1H-pyrazole-4-yl)-5-(3 R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidine-7-amine(SCH90 0776, CAS 891494-63-6); 5-(3-fluorophenyl)-3-U Raidothiophen-2-carboxylic acid N-[(S)-piperidine-3-yl]amide (A ZD7762, CAS 860352-01-8); 4-[((3S)-1-Azabishic [2.2.2]octa-3-yl)amino]-3-(1H-benzimidazole-2- Il-6-chloroquinoline-2(1H)-one (CHIR124, CAS 40516) 8-58-3); 7-aminodactinomycin (7-AAD), isogranulatide, de Bromohymenialdisine; N-[5-bromo-4-methyl-2-[(2S)-2-morpho Linylmethoxyphenyl-N'-(5-methyl-2-pyradinyl)urea (LY26) 03618, CAS 911222-45-2); sulforaphane (CAS 4478- 93-7,4-methylsulfinylbutylisothiocyanate); 9,10,11,12 -Tetrahydro-9,12-epoxy-1H-diindro[1,2,3-fg:3',2 ',1'-kl]pyrrolo[3,4-i][1,6]benzodiazosin-1,3(2H)- Zeon (SB-218078, CAS 135897-06-2); and TAT-S2 16A(YGRKKRRQRRRLYRSPAMPENL) and CBP501((dB pa)sws(d-Phe-F5)(d-Cha)rrrqrr); and (αR)-α- Amino-N-[5,6-dihydro-2-(1-methyl-1H-pyrazole-4-yl)- 6-Oxo-1H-pyrrolo[4,3,2-ef][2,3]benzodiazepine-8-yl ]-Cyclohexaneacetamide (PF-0477736).

[0318] 3-Phosphoinositide-dependent kinase-1 (PDK1 or PDPK1) inhibitors: 7-2 -amino-N-[4-[5-(2-phenantrenyl)-3-(trifluoromethyl)- 1H-pyrazole-1-yl]phenyl]acetamide (OSU-03012, CAS 742112-33-0); Pyrrolidine-1-carboxylic acid (3-{5-bromo-4-[ 2-(1H-imidazole-4-yl)-ethylamino]-pyrimidine-2-ylamino }-phenyl)amide (BX912, CAS 702674-56-4); and 4- Decyl-N-1,3,4-thiadiazole-2-ylbenzenesulfonamide (PHT -427, CAS 1191951-57-1).

[0319] Protein kinase C (PKC) activators: bryostatin I (bryo-1) and so Trastaurin (AEB071).

[0320] B-RAF inhibitor: Regorafenib (BAY73-4506, CAS 755037-) 03-7); Zubizanib (AV951, CAS 475108-18-0); Vemurafe Nib (Zelboraf®, PLX-4032, CAS 918504-65) -1); 5-[1-(2-hydroxyethyl)-3-(pyridine-4-yl)-1H-py Razole-4-yl]-2,3-dihydroinden-1-one oxime (GDC-087 9. CAS 905281-76-7); 5-[2-[4-[2-(dimethylamino)e Toxyphenyl]-5-(4-pyridinyl)-1H-imidazole-4-yl]-2, 3-Dihydro-1H-indene-1-one oxime (GSK2118436 or SB59) 0885); (5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3- Oxo-2,3-dihydro-1H-isoindole-1-yl)-1H-benzimidazol Methyl(XL-2-yl)carbamate (+ / -)-(XL-281 and BMS90866) (also known as 2) and N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridyl (-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide ( (Also known as PLX4720).

[0321] C-RAF inhibitors: sorafenib (Nexavar®); 3-(dimethylamine) Mino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]- Benzamide (ZM336372, CAS 208260-29-1); and 3-(1- Cyano-1-methylethyl)-N-[3-[(3,4-dihydro-3-methyl-4-oxy So-6-quinazolinyl)amino]-4-methylphenyl]-benzamide (AZ628, CAS 1007871-84-2).

[0322] Human granulocyte colony-stimulating factor (G-CSF) modifier: Filgrastim (Neupog en(registered trademark); Sunitinib malate (Sutent(registered trademark)); Pegylglass Tim (Pegilgrastim) (Neulasta®) and quizartinib (AC220, CAS 950769-58-1).

[0323] RET inhibitors: Sunitinib malate (Sutent®); Vandetanib (C aprelsa®); Motesanib diphosphate (AMG706, CAS 857) 876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indole-6) -yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, P As described in the CT publication number International Publication No. 02 / 066470 pamphlet); Sora Fenib (BAY 43-9006); Regorafenib (BAY 73-4506, CAS) 755037-03-7); and danucertib (PHA-739358).

[0324] FMS-like tyrosine kinase 3 (FLT3) inhibitor or CD135: sunitinib malate (Sutent®), quizartinib (AC220, CAS 950769-5) 8-1); Sulfate N-[(1-methyl-4-piperidinyl)methyl]-3-[3-(Trifol [Luoromethoxy)phenyl]-imidazo[1,2-b]pyridazine-6-amine (SGI -1776, CAS 1173928-26-1); and Bargatev (BIBF1120 (CAS 928326-83-4).

[0325] c-KIT inhibitors: Pazopanib (Votrient®); Dovitinib dilactic acid (TKI258, CAS 852433-84-2); Motesanib diphosphate (AMG7) 06, CAS 857876-30-3, N-(2,3-dihydro-3,3-dimethyl- 1H-Indole-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinyl Carboxamide, PCT Publication Number International Publication No. 02 / 066470, pamphlet (as described); Macitinib (Masivet(registered trademark)); Regorafenib (BAY 73-4506, CAS 755037-03-7); tivozanib (AV951, CAS 475108-18-0); Batalanib dihydrochloride (PTK787, CAS 21214) 1-51-0); Teratinib (BAY57-9352, CAS 332012-40-5) ); Foretinib (GSK1363089, formerly XL880, CAS 849217- 64-7); Sunitinib malate (Sutent®); Quizartinib (AC2 20. CAS 950769-58-1); Axitinib (Inlyta®) Dasatinib (BMS-345825); and sorafenib (Nexavar (registered trademark)) ))

[0326] Bcr / Abl kinase inhibitors: Imatinib (Gleevec®); Inilol Tinib hydrochloride; nilotinib (Tasigna®); dasatinib (BMS-34) 5825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafeti Nib (INNO406); Danucertib (PHA-739358), AT9283 (CA S 1133385-83-7); Salacatinib (AZD0530); and N-[2-[ (1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)- 2-Pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene-1,4-imi [-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16-3).

[0327] IGF-1R inhibitor: lincitonib (OSI-906); [7-[trans-3-[ (azetidine-1-yl)methyl]cyclobutyl]-5-(3-benzyloxyphenyl) )-7H-pyrrolo[2,3-d]pyrimidine-4-yl]amine (AEW541, CAS 475488-34-7);[5-(3-benzyloxyphenyl)-7-[tran s-3-[(pyrroridine-1-yl)methyl]cyclobutyl]-7H-pyrrolo[2,3- d] Pyrimidine-4-yl]amine (ADW742 or GSK552602A, CAS 475488-23-4);(2-[[3-bromo-5-(1,1-dimethylethyl)- 4-Hydroxyphenyl]methylene]-propanedinitrile (thirophostine AG1024) CAS 65678-07-1); 4-[[(2S)-2-(3-chlorophenyl)- 2-Hydroxyethyl]amino]-3-[7-methyl-5-(4-morpholinyl)-1H -Benzimidazole-2-yl]-2(1H)-pyrimidinone (BMS536924, CAS 468740-43-4); 4-[2-[4-[[(2S)-2-(3-chloro Phenyl)-2-hydroxyethyl]amino]-1,2-dihydro-2-oxo-3-p [Ridinyl]-7-methyl-1H-benzoimidazole-5-yl]-1-piperazine pro Pannitrile (BMS554417, CAS 468741-42-6); (2S)-1 -[4-[(5-cyclopropyl-1H-pyrazole-3-yl)amino]pyrrolo[2, [1-f][1,2,4]triazine-2-yl]-N-(6-fluoro-3-pyridinyl) )-2-methyl-2-pyrrolidinecarboxamide (BMS754807, CAS 100 1350-96-4); picropodophyllotoxin (AXL1717); and nordihydr Logaleacetic acid.

[0328] IGF-1R antibodies: Figitumumab (CP751871); Cizutumumab (IMC-A 12); Ganitumumab (AMG-479); Lobatumumab (SCH-717454); Dalo Tuzumab (MK0646); R1507 (available from Roche); BIIB022 ( Available from Biogen; and MEDI-573 (available from MedImmune). ).

[0329] MET inhibitor: Cabozantinib (XL184, CAS 849217-68-1); Oletinib (GSK1363089, formerly XL880, CAS 849217-64-) 7); Tivantinib (ARQ197, CAS 1000873-98-2); 1-(2- Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinoline-4-ylox (C)pyridine-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-carboxamide (AMG 458); crizotinib (Xalk ori(registered trademark), PF-02341066); (3Z)-5-(2,3-dihydro- 1H-Indole-1-ylsulfonyl)-3-({3,5-dimethyl-4-[(4-methyl [Tylpiperazine-1-yl)carbonyl]-1H-pyrrole-2-yl}methylene)-1 ,3-dihydro-2H-indole-2-one(SU11271);(3Z)-N-(3 -chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazine-1- [Iyl)carbonyl]-1H-pyrrole-2-yl}methylene)-N-methyl-2-oxo Indoline-5-sulfonamide (SU11274); (3Z)-N-(3-chlorophenate) (Nyl)-3-{[3,5-dimethyl-4-(3-morpholine-4-ylpropyl)-1H Pyrrole-2-yl]methylene}-N-methyl-2-oxoindoline-5-sulfone amide (SU11606); 6-[difluoro[6-(1-methyl-1H-pyrazole- 4-yl)-1,2,4-triazolo[4,3-b]pyridazine-3-yl]methyl]- Quinoline (JNJ38877605, CAS 943540-75-8); 2-[4-[ 1-(quinoline-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]p [Radin-6-yl]-1H-pyrazole-1-yl]ethanol (PF04217903) CAS 956905-27-4); N-((2R)-1,4-dioxan-2-yl Methyl)-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5 -Oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-yl]s Rufamide (MK2461, CAS 917879-39-1); 6-[[6-(1-Me (Tyl-1H-pyrazole-4-yl)-1,2,4-triazolo[4,3-b]pyridadi [3-Ilthio]-Quinoline (SGX523, CAS 1022150-57-7) ; and (3Z)-5-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-[ [3,5-dimethyl-4-[[(2R)-2-(1-pyrrolidinylmethyl)-1-pyrroli [Dinyl]carbonyl]-1H-pyrrole-2-yl]methylene]-1,3-dihydro-2 H-Indole-2-one (PHA665752, CAS 477575-56-7).

[0330] Epidermal growth factor receptor (EGFR) inhibitor: Erlotinib hydrochloride (Tarceva (registered) Trademark), Gefitinib (Iressa (registered trademark)); N-[4-[(3-chloro-4 -Fluorophenyl)amino]-7-[[(3''S'')-tetrahydro-3-furani [Lu]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Tovo k(registered trademark)); vandetanib (Caprelsa(registered trademark)); lapatinib (Ty kerb(registered trademark)); (3R,4R)-4-amino-1-((4-((3-methoxy Phenyl)amino)pyrrolo[2,1-f][1,2,4]triazine-5-yl)methyl ) Piperidine-3-ol (BMS690514); Canertinib dihydrochloride (CI-10 33); 6-[4-[(4-ethyl-1-piperazinyl)methyl]phenyl]-N-[( 1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidine-4-amine ( AEE788, CAS 497839-62-0); Mbritinib (TAK165); Pe Litinib (EKB569); Afatinib (BIBW2992); Neratinib (HKI- 272); N-[4-[[1-[(3-fluorophenyl)methyl]-1H-indazo [Lu-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazine- 6-yl]-carbamic acid, (3S)-3-morpholinyl methyl ester (BMS599 626); N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-[[ (3aα,5β,6aα)-Octahydro-2-methylcyclopenta[c]pyrrole-5 -yl-methoxy-4-quinazolineamine (XL647, CAS 781613-23) -8); and 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[ 2,3-d]pyrimidine-6-yl]phenol (PKI166, CAS 18772) 4-61-4).

[0331] EGFR antibodies: Cetuximab (Erbitux®); Panitumumab (Vec tibix(registered trademark); matsuzumab (EMD-72000); trastuzumab (He rceptin(registered trademark); nimotuzumab (hR3); zaltumumab; TheraC IM h-R3;MDX0447(CAS 339151-96-1);and ch806 (mAb-806, CAS 946414-09-1).

[0332] mTOR inhibitors: Temsirolimus (Torisel®); Ridahololimus ( Officially known as deferolimus, (1R,2R,4S)-4-[(2R)-2[ (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,2 6E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dihydroxy Toxy-15,17,21,23,29,35-Hexamethyl-2,3,10,14,2 0-Pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04, 9 hexatriaconta-16,24,26,28-tetraen-12-yl]propyl -2-methoxycyclohexyldimethylphosphinate, AP23573 and MK86 also known as 69, described in PCT Publication No. WO 03 / 064383 pamphlet ; everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3); (5-{2,4-bis[(3S)-3-methylmorpholin- 4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)metha nol (AZD8055), 2-amino-8-[trans-4-(2-hydroxyethoxy )cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido 2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS 1013 101-36-4); N 2 -[1,4-dioxo-4-[[4-(4-oxo-8-phen yl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]buty l]-L-arginylglycyl-L-α-aspartylL-serine-, inner salt (SF1 126, CAS 936487-67-1); and N-[4-[[[3-[(3,5-di methoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]- 3-methoxy-4-methyl-benzamide (XL765, also known as SAR245409 ); and (1r,4r)-4-(4-amino-5-(7-methoxy-1H-ind ol-2-yl)imidazo[1,5-f][1,2,4]triazin-7-yl)cyclo Hexanecarboxylic acid (OSI-027).

[0333] Mitogen-activated protein kinase (MEK) inhibitor: XL-518 (GDC-0 Also known as 973, Cas No. 1029872-29-4, ACC Corp. Available from .); selumetinib (5-[(4-bromo-2-chlorophenyl)amino] -4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazo Also known as 6-carboxamide, AZD6244, or ARRY 142886. (as described in the PCT Publication Number International Publication No. 2003077914 pamphlet); 2- [(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3 ,4-difluorobenzamide (also known as CI-1040 or PD184352) (as described in the PCT Publication Number International Publication No. 2000035436 pamphlet); N- [(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-f Luoro-4-iodophenyl)amino]-benzamide (also known as PD0325901) It is listed in the PCT Publication Number International Publication No. 2002006213 pamphlet; 2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile( Also known as U0126, it is described in U.S. Patent No. 2,779,780);N -[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6- Methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropane Sulfonamide (also known as RDEA119 or BAY869766, PCT publicly available) As described in the international publication number 2007014011; (3S, 4R, 5) Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy- 3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacycloth [Tradecine-1,7(8H)-Dion] (also known as E6201, PCT public listing number country) As described in the brochure published in 2003076424); 2'-amino-3'-me Toxiflavone (also known as PD98059, manufactured by Biaffin GmbH&Co., Ltd.) Available from KG, Germany); vemurafenib (PLX-4032, CAS 9 18504-65-1); (R)-3-(2,3-dihydroxypropyl)-6-fluor Ro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d Pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 103555) 5-63-5); Pimasertib (AS-703026, CAS 1204531-26- 9); Trametinib dimethyl sulfoxide (GSK-1120212, CAS 1204) 531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2- Hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3 -Carboxamide (AZD 8330); and 3,4-difluoro-2-[(2-fluorine [4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-o Xo-[1,2]oxadinan-2-yl)methyl]benzamide (CH 498765 5 or Ro 4987655).

[0334] Alkylating agents; oxaliplatin (Eloxatin®); temozolomide Temodar (registered trademark) and Temodal (registered trademark); Dactinomycin (A Cutinomycin-D, also known as Cosmegen®); melphalan (L-PAM, L-sarcolicin and phenylalanine mustard, Alkeran ( Also known as (registered trademark); Altretamine (hexamethylmelamine (HMM), He Also known as xalen (registered trademark); carmustine (BiCNU (registered trademark)) ; Bendamustine (Treanda (registered trademark)); Busulfen (Busulfex ( (Registered trademark) and Myleran (Registered trademark); Carboplatin (Paraplatin (Registered Trademark); Romustine (also known as CCNU and CeeNU (Registered Trademark)); Cisplatin (CDDP, Platinol® and Platinol®) (Also known as AQ); Chlorambucil (Leukeran (registered trademark)); C Clophosphamide (Cytoxan® and Neosar®); Daca Luvazin (DTIC, DIC and imidazole carboxamide, DTIC-Dome ( Also known as (registered trademark); Altretamine (hexamethylmelamine (HMM), He Also known as xalen (registered trademark); ifosfamide (Ifex (registered trademark)) Prednumustine; Procarbazine (Matulan e(registered trademark)); Mechloretamine (nitrogen mustard, mustine and mechloretamine hydrochloride) Streptozocin, also known as loroetamin or Mustargen®; (Zanosar®); Thiotepa (thiophosphoamide, TESPA and TSP A, also known as Thioplex (registered trademark); cyclophosphamide (Endo xan(registered trademark), Cytoxan(registered trademark), Neosar(registered trademark), Pro Cytox®, Revimmune®; and Bendamustine HCl l(Treanda(registered trademark)).

[0335] Aromatase inhibitors: exemestane (Aromasin®); retrozo Ru (Femara (registered trademark)); and Anastrozole (Armidex (registered trademark)) ).

[0336] Topoisomerase I inhibitors: Irinotecan (Camptosar®); Topo Tecan hydrochloride (Hycamtin®); and 7-ethyl-10-hydroxyca Nputotecin (SN38).

[0337] Topoisomerase II inhibitors: Etoposide (VP-16 and etoposide phosphate, Top osar (registered trademark), VePesid (registered trademark), and Etopophos (registered trademark) )); Teniposide (VM-26, Vumon®); and Tafulposide.

[0338] DNA synthesis inhibitors: Capecitabine (Xeloda®); gemcitabine hydrochloride (Gemzar(registered trademark)); Neralabine ((2R,3S,4R,5R)-2-(2- (Amino-6-methoxy-purine-9-yl)-5-(hydroxymethyl)oxolane-3 ,4-diol, Arranon® and Atriance®); and bisapacitabine (1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-4 -(palmitoylamino)pyrimidine-2(1H)-one).

[0339] Folic acid antagonist or folic acid antimetabolite: Trimethrexate glucuronide (Neut rexin(registered trademark); pyritrexim isethionate (BW201U); pemetre Xed (LY231514); Larcitrexed (Tomudex®); and Methotrexate (Rheumatrex®, Trexal®).

[0340] Immunomodulators: Aftuzumab (available from Roche®); Pegfilgra Stim (Neulasta (registered trademark)); Lenalidomide (CC-5013, Revli mid(registered trademark); Thalidomide (Thalomid(registered trademark)), Actimide ( CC4047); and IRX-2 (Interleukin 1, Interleukin 2 and Inter - A mixture of human cytokines including feron-γ, CAS 951209-71-5, IR (Available from X Therapeutics)

[0341] G protein-coupled somatostatin receptor inhibitor: Octreotide (Octreotide acetate) Sandostatin (registered trademark) and Sandostatin, also known as Do. LAR (registered trademark); lanreotide acetate (CAS 127984-74-1); segu Lithide (MK678); vapreotide acetate (Sanvar®); and cyclo( D-Trp-Lys-Abu-Phe-MeAla-Tyr)(BIM23027).

[0342] Interleukin-11 and synthetic interleukin-11 (IL-11): Oprelbe Kin (Neumega (registered trademark)).

[0343] Erythropoietin and synthetic erythropoietin: Erythropoietin (Epogen (Registered) (Trademark) and Procrit (Registered Trademark); Darbepoetin alpha (Aranesp( (Registered Trademark)); Peginesatide (Hematide (Registered Trademark)); and polyethylene glyceride EPO (Micera®) covalently coupled to the call.

[0344] Histone deacetylase (HDAC) inhibitors: Boninostat (Zolinza (Registered (Trademark); Romidepsin (Istodax (Registered Trademark)); Trecostatin A (TSA) ); oxamfratin; vorinostat (Zolinza®, suberoylani) Lidohydroxamic acid; pyroxamide (siberoyl-3-aminopyridineamide hydroxamic acid) Sam acid; Trapoxin A (RF-1023A); Trapoxin B (RF-10238) ;Cyclo[(αS,2S)-α-amino-η-oxo-2-oxylanoctanoyl-O -methyl-D-tyrosyl-L-isoleucyl-L-prolyl](Cyl-1);cyclo[ (αS,2S)-α-amino-η-oxo-2-oxiranoctanoyl-O-methyl- D-Tyrosyl-L-Isoleucyl-(2S)-2-Piperidinecarbonyl](Cyl-2 );cyclic [L-alanyl-D-alanyl-(2S)-η-oxo-L-α-aminooxy Lanoctanoyl-D-prolyl](HC-toxin); cyclo[(αS,2S)-α-amine] No-η-oxo-2-oxylanoctanoyl-D-phenylalanyl-L-leucyl- (2S)-2-piperidinecarbonyl](WF-3161); Chlamydosin ((S)-ring (2-methylalanyl-L-phenylalanyl-D-prolyl-η-oxo-L-α- Aminooxyranoctanoyl); Apicidine (Cyclo(8-oxo-L-2-aminode Canoyl-1-methoxy-L-tryptoyl-L-isoleucyl-D-2-piperidine Rubonyl); Romidepsin (Istodax®, FR-901228); 4- Phenylbutyrate; Spircostatin A; Milproine (Valproic Acid); Entinostatin tt(MS-275, N-(2-aminophenyl)-4-[N-(pyridine-3-yl- Methoxycarbonyl)-amino-methyl]-benzamide); and depdecine (4,5: 8,9-Dianhydro-1,2,6,7,11-Pentadeoxy-D-Threo-D-id (-Undeca-1,6-dienitole).

[0345] Biological reaction modifiers: interferon, interleukin, colony-stimulating factor, mono Clonal antibodies, vaccines (therapeutic and prophylactic), gene therapy and nonspecific immunomodulators Which medications are included? Interferon alpha (Intron®, Rofer son(registered trademark)-A); interferon beta; interferon gamma; inter - Leukin-2 (IL-2 or Aldesleukin, Proleukin®); Philgrastim (Neupogen®); Salgramostim (Leukin e(registered trademark)); Erythropoietin (epoetin); Interleukin-11 (Ople) Rubequine; Imiquimod (Aldara (registered trademark)); Lenalidomide (Revlimi d(registered trademark)); Rituximab (Rituxan(registered trademark)); Trastuzumab (H erceptin(registered trademark); Bacillus calmette-Guérin bacilli mette-guerin) (theraCys (registered trademark) and TICE (registered trademark)) BCG; Ergamisol (registered trademark); and Deniroykin Dift Tox (Ontak (registered trademark)).

[0346] Plant alkaloids: Paclitaxel (Taxol and Onxal (trademarks)); protein Phytoconjugated paclitaxel (Abraxane®); vinblastine (vin sulfate) Blastin, vincaloycoblastine and VLB, Alkaban-AQ (registered trademark) and Also known as Velban (registered trademark); vincristine (vincristine sulfate) Also known as LCR and VCR, Oncovin® and Vincasa r Pfs(registered trademark); Vinorelbine (Navelbine(registered trademark)).

[0347] Taxane anti-cancer drugs: Paclitaxel (Taxol®); Docetaxel ( Taxotere (registered trademark); Cabazitaxel (Jevtana (registered trademark), 1- Hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytaxa-1 1-En-2α,4,13α-triyl-4-acetate-2-benzoate-13-[ (2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydrox C-3-phenylpropanoate); and larotaxel (benzoic acid (2α,3ξ,4α, 5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R ,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-fu Phenylpropanoyl(oxy)-1-hydroxy-9-oxo-5,20-epoxy-7 ,19-cyclotaxa-11-en-2-yl).

[0348] Heat shock protein (HSP) inhibitor: Tanespimycin (17-alkylamino- Also known as 17-demethoxygeldanamycin, KOS-953, and 17-AAG, (Available from SIGMA, as described in U.S. Patent No. 4,261,989) Letaspimycin (IPI504), Ganetespib (STA-9090); [6-chloro Ro-9-(4-methoxy-3,5-dimethylpyridine-2-ylmethyl)-9H-purine -2-ylamine (BIIB021 or CNF2024, CAS 848695-25) -0);trans-4-[[2-(aminocarbonyl)-5-[4,5,6,7-teto (Lahydro-6,6-dimethyl-4-oxo-3-trifluoromethyl)-1H-indazo [I-1-yl]phenyl]amino]cyclohexylglycine ester (SNX5422) or PF04929113, CAS 908115-27-5); and 17-dimethyl Minoethylamino-17-demethoxygeldanamycin (17-DMAG).

[0349] Thrombopoietin (TpoR) agonist: Eltrombopag (SB497115, P romacta (registered trademark) and Revolade (registered trademark); and Romiprostim (Nplate (registered trademark)).

[0350] Demethylating agents: 5-azacitidine (Vidaza®); and decitabine (D acogen (registered trademark).

[0351] Cytokine: Interleukin-2 (also known as aldesleukin and IL-2) Proleukin (registered trademark); Interleukin-11 (oprelbekin) Also known as Neumega®; and alpha interferon alpha (IFN-Alpha, Intron (registered trademark) and Roferon-A (registered trademark) (Also known as...).

[0352] 17α-hydroxylase / C17,20-lyase (CYP17A1) inhibitor: Acetate Virateron (Zyitga® registered trademark).

[0353] Various cytotoxic drugs: Arsenic trioxide (Trisenox®); Asparagus -ase (L-asparaginase, Erwinia L-asparaginase) Also known as Elspar® and Kindrolase®; and asparaginase black leg disease fungus (Erwinia Chrysanthemi) (Er winaze (registered trademark).

[0354] CC chemokine receptor 4 (CCR4) antibody: mogamulizumab (Potelligen) t(registered trademark).

[0355] CD20 antibodies: Rituximab (Rituxan® and MabThera®) (Registered Trademark)); and Tositumomab (Bexxar (Registered Trademark)); and Ofatumumab (A rzerra(registered trademark).

[0356] CD20 antibody drug conjugate: Ibritumomab tiuxetan (Zevalin) (Registered trademark)); and Toshitsumo Mabu.

[0357] CD22 antibody drug conjugate: Inotuzumab ozogamicin (CMC-544 and Also known as WAY-207294, Hangzhou Sage Chemical (Available from Co., Ltd.)

[0358] CD30 mAb-cytotoxic conjugate: brentuximab vedotin (Adcetr ix (registered trademark).

[0359] CD33 antibody drug conjugate: gemtuzumab ozogamicin (Mylotarg) Registered trademark).

[0360] CD40 antibody: Dasetuzumab (also known as SGN-40 or huS2C6, Se (Available from Attle Genetics, Inc.)

[0361] CD52 antibody: Alemtuzumab (Campath®).

[0362] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS number 915296-00-3) ).

[0363] CTLA-4 antibody: Tremelimumab (IgG2 monoclonal antibody available from Pfizer) Naru antibody, formerly known as tisilimunab, CP-675,206); and ipilim Mab (CTLA-4 antibody, also known as MDX-010, CAS number 477202-) 00-9).

[0364] TPH inhibitor: telototristat.

[0365] PARP (Poly-ADP-ribose polymerase) inhibitor: Olaparib (Lynparza) ), rubraparibu (Rubraca), neaparibu (Zeluja), thalassoparib, belly Paribu.

[0366] In particular, the present invention relates to radionuclides 177 Lu (Lutetium-177) and as defined herein It is formed by a somatostatin receptor-binding peptide linked to a chelating agent, as described above. A combination of complexes or combination therapy, or octreotide, lanreotide, bap Loreotide, Pasireotide, Saturote, Everolimus, Temozolomide, Terotrista , sunitinib, sulfatinib, ribociclib, entinostat, pazopanib and As defined herein, in combination with one of the further therapeutic agents selected from the group consisting of olaparib. We provide combinations of medicinal aqueous solutions or combination therapies as described.

[0367] Methods of treating cancer In one embodiment, the present disclosure relates to a therapeutic agent or cancerous tumor whose growth is inhibited. Compositions or formulations containing combinations disclosed herein that reduce or eliminate Regarding the target in vivo treatment using a combination of methods.

[0368] In some embodiments, PD-1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, G ITR agonists, TGF-β inhibitors, and IL-15 / IL15RA conjugates are described herein. It shall be administered or used in accordance with the disclosed drug regimen.

[0369] In one embodiment, the combination disclosed herein is favored for in vivo cancer treatment. It is suitable. For example, a combination can be used to inhibit the growth of cancerous tumors. The combination is Standard treatments for treating the disorders disclosed herein (for example, cancer or infectious disorders) (for example), vaccines (e.g., therapeutic cancer vaccines), cell therapy, radiation therapy, surgery or It may also be used in combination with one or more other therapeutic agents or modalities. For example, To achieve antigen-specific enhancement of immunity, the combination may be administered together with the target antigen. The combinations disclosed herein may be administered in any order or simultaneously.

[0370] In another embodiment, the subject is treated, for example, in a state of excessive growth or impairment (e.g.) The present invention provides a method for reducing or improving cancer, such as solid tumors, hematological malignancies, soft tissue tumors, or metastatic lesions. The method involves applying three or more (e.g., four or more) therapeutic agents disclosed herein to the subject. Or a combination including a composition or formulation containing the combination disclosed herein, for example For example, administering the medication in accordance with the drug regimen disclosed herein.

[0371] As used herein, the term "cancer" refers to a pathological type or stage of invasiveness. Furthermore, all types of cancerous growth or carcinogenic processes, metastatic tissue, or malignantly transformed cells. This includes tissues or organs. Examples of cancerous disorders include solid tumors, hematological malignancies, and soft tissue Examples of solid tumors include, but are not limited to, histological tumors and metastatic lesions. Organs, lungs, breasts, lymphatic system, gastrointestinal system (e.g., colon), urogenital system (e.g., kidneys, urinary tract cancer) (bladder epithelial cells), prostate, CNS (e.g., brain, nerve or glial cells), skin, pancreas and Malignant tumors of various organ systems, including those affecting the pharynx, such as sarcomas and carcinomas (adenocarcinomas and squamous tumors). Adenocarcinomas include most colorectal cancers, rectal cancers, renal cell carcinomas, and liver cancers. Examples of malignant tumors include non-small cell lung cancer, small intestine cancer, and esophageal cancer. Squamous cell carcinoma is also included. Examples include malignant tumors of the lungs, esophagus, skin, head and neck region, oral cavity, anus, and neck. The aforementioned metastatic lesions of cancer can also be treated or prevented using the methods and compositions of the present invention. .

[0372] As used herein, the term “subject” is intended to include humans and non-human animals. It can be done.

[0373] The combination therapies described herein include one or more additional therapeutic agents, for example, one or more Anticancer drugs, cytotoxic drugs or cell division inhibitors, hormone therapy, vaccines and / or other immunosuppressants The present invention may include compositions that are formulated and / or administered simultaneously with epidemic therapy. In embodiments, the combination includes surgical procedures, radiation therapy, cryosurgery, and / or hyperthermia. It is further administered or used in combination with other therapeutic modalities, including [unspecified]. Combination therapy advantageously utilizes lower doses of therapeutic agents, thereby enabling various single treatments. Potential toxicity or complications associated with drug therapy can be avoided.

[0374] When administered in combination, the therapeutic agents are used individually, for example, as monotherapy. The amount or dosage of each drug is greater than, less than, or the same as the amount or dosage of each drug. It may be administered by [method]. In a particular embodiment, the amount or dosage of the therapeutic agent administered is individually For example, less than the amount or dosage of each drug used as monotherapy (for example, less than Also 20%, at least 30%, at least 40%, or at least 50%. Other embodiments In this case, the amount or dose of the therapeutic agent that produces the desired effect (e.g., cancer treatment) is less No (for example, at least 20%, at least 30%, at least 40%, or at least (50% less).

[0375] Pharmaceutical composition In another embodiment, the present invention is formulated with a pharmaceutically acceptable carrier as described herein. One or more of the listed therapeutic agents, for example, 2, 3, 4, 5, 6, 7, 8 or more The present invention provides compositions containing, for example, pharmaceutically acceptable compositions. "Pharmacologically acceptable carriers" include any physiologically compatible solvent, dispersion medium, etc. It contains tonic agents and absorption retarders. The carriers are intravenous, intramuscular, subcutaneous, parenteral, rectal, and spinal. It may be suitable for medulla or epidermal administration (e.g., by injection or infusion).

[0376] The composition of the present invention may take various forms. For example, it may take the form of a liquid solution (e.g., Liquids, semi-solids such as solutions for injection and infusion, dispersions or suspensions, liposomes and suppositories, etc. Examples include solid-state medication forms. The preferred form depends on the intended method of administration and therapeutic application. It exists. Typical compositions are in the form of injection or injectable solutions. In certain embodiments, The method of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular). In its form, the composition is administered by intravenous infusion or injection. In another embodiment, The composition is administered by intramuscular or subcutaneous injection.

[0377] The terms "parenteral administration" and "administered parenterally" are used herein in the following sense: This refers to methods of administration other than intestinal and local administration, usually by injection, and without limitation, including intravenous and intramuscular. Internal, intraarterial, intrathecal, intrasacral, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, recurrent These include intranodal, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions.

[0378] Therapeutic compositions are typically sterile and stable under manufacturing and storage conditions. It must be. The composition is a solution, microemulsion, dispersion, liposome or other high It can be formulated as an ordered structure suitable for the antibody concentration. The sterile injection solution is prepared in the required amount. The active compound (i.e., antibody or antibody portion) is placed in a suitable solvent, and if necessary, the components listed above are added. It can be prepared by compounding one or a combination of these ingredients, followed by sterile filtration. Generally The dispersion is sterile and contains a basic dispersion medium and other necessary components from those listed above. It is prepared by incorporating an active compound into a medium. Sterilization for the preparation of sterile injection solutions. In the case of powders, a preferred preparation method is to pre-sterilize the powder of the active ingredient + any additional desired ingredients. This involves vacuum drying and freeze-drying, which are produced from the passed solution. The appropriate fluidity of the solution is: For example, the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and the interface. It can be maintained by the use of activators. Drugs that delay absorption, such as monostearate. By including phosphates and gelatin in the composition, sustained absorption of the injectable composition is achieved. It is possible.

[0379] In some embodiments, PD-1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, G ITR agonists, TGF-β inhibitors, IL-15 / IL-15RA complexes, or these Any combination may be administered to the target as described herein (e.g., intravenous administration). It can be formulated into a suitable formulation (e.g., an administration formulation or dosage form) for )

[0380] In some embodiments, PD-1 inhibitors described herein (e.g., anti-PD-1) The antibody molecule or composition may be administered to the subject as described herein (e.g., intravenously) It can be formulated into a suitable formulation (e.g., an administration formulation or dosage form) for administration.

[0381] In certain embodiments, the formulation is an active ingredient formulation. In other embodiments, the formulation is For example, a lyophilized or dried lyophilized formulation obtained from an active ingredient formulation. In other embodiments, The formulation is, for example, a reconstituted formulation reconstituted from a lyophilized formulation. In this embodiment, the formulation is a liquid formulation. In some embodiments, the formulation (e.g., active ingredient formulation) These include PD-1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, GITR agonists, and TG. Includes F-β inhibitors, IL-15 / IL-15RA complexes, or any combination thereof. .

[0382] In some embodiments, the formulation is an active ingredient formulation. In some embodiments, the formulation ( For example, the active pharmaceutical ingredient (API) contains a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) and a buffer. nothing.

[0383] In some embodiments, the formulation (e.g., the active ingredient formulation) is 10-50 mg / mL, for example 15~50mg / mL, 20~45mg / mL, 25~40mg / mL, 30~35m g / mL, 25-35 mg / mL or 30-40 mg / mL, for example 15 mg / mL, 2 0mg / mL, 25mg / mL, 30mg / mL, 33.3mg / mL, 35mg / mL PD-1 inhibitors available at concentrations of 40 mg / mL, 45 mg / mL, or 50 mg / mL (e.g., an anti-PD-1 antibody molecule) is included in certain embodiments. In certain embodiments, a PD-1 inhibitor (e.g.) For example, an anti-PD-1 antibody molecule is concentrated at 30-35 mg / mL, for example, 33.3 mg / mL. It exists in degrees.

[0384] In some embodiments, the formulation (e.g., the active ingredient formulation) is histidine (e.g., histidine The buffer contains a din buffer. In certain embodiments, the buffer contains a din buffer (e.g., histidine). The buffer solution can be 1mM to 20mM, for example, 2mM to 15mM, 3mM to 10mM, or 4mM. ~9mM, 5mM~8mM, or 6mM~7mM, for example, 1mM, 2mM, 3mM, 4mM , 5mM, 6mM, 6.7mM, 7mM, 8mM, 9mM, 10mM, 11mM, 12m M, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM or 20 It is present at a concentration of mM. In some embodiments, a buffer (e.g., histidine buffer) is used. It is present at a concentration of 6 mM to 7 mM, for example, 6.7 mM. In other embodiments, buffer The agent (e.g., histidine buffer) is 4-7, e.g., 5-6, e.g., 5, 5.5, or 6 It has a pH. In some embodiments, the buffer (e.g., histidine buffer) is 5~ 6. For example, having a pH of 5.5. In certain embodiments, the buffer is 6 mM to 7 mM. It contains histidine at a concentration of (e.g., 6.7 mM) and has a p of 5-6 (e.g., 5.5). H.

[0385] In some embodiments, the formulation (e.g., the active ingredient formulation) is 30-35 mg / mL, for example A PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 33.3 mg / mL ; and containing histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 ( For example, it includes a buffer having a pH of 5.5).

[0386] In some embodiments, the formulation (e.g., the active ingredient formulation) further comprises carbohydrates. In some embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (For example, sucrose) is 50 mM to 150 mM, for example, 25 mM to 150 mM, 50 mM ~100mM, 60mM ~90mM, 70mM ~80mM, or 70mM ~75mM, For example, 25mM, 50mM, 60mM, 70mM, 73.3mM, 80mM, 90mM, It is present at concentrations of 100 mM or 150 mM. In some embodiments, the formulation is 70 mM It contains carbohydrates or sucrose present at concentrations of M to 75 mM, for example, 73.3 mM.

[0387] In some embodiments, the formulation (e.g., the active ingredient formulation) is 30-35 mg / mL, for example A PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 33.3 mg / mL ; Contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 (for example (i) A buffer having a pH of 5.5; and a concentration of 70 mM to 75 mM, for example, 73.3 mM. Contains carbohydrates or sucrose present in a certain degree.

[0388] In some embodiments, the formulation is an active ingredient formulation. In some embodiments, the formulation ( For example, active pharmaceutical ingredients (APIs) include PD-1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, and GIT R agonist, TGF-β inhibitor, IL-15 / IL-15RA complex, or any of these. This includes combinations and cushioning materials.

[0389] In some embodiments, the formulation (e.g., the active ingredient formulation) further comprises a surfactant. In some embodiments, the surfactant is polysorbate 20. Furthermore, the surfactant or polysorbate 20 is present in a concentration of 0.005% to 0.025% (w / w), For example, 0.0075%~0.02% or 0.01%~0.015% (w / w), for example 0 0.005%, 0.0075%, 0.01%, 0.013%, 0.015%, or 0.02% It exists at a concentration of (w / w). In some embodiments, the formulation is 0.01%~0.01 A surfactant or polysorbate 2 present at a concentration of 5%, for example, 0.013% (w / w) Includes 0.

[0390] In some embodiments, the formulation (e.g., the active ingredient formulation) is 30-35 mg / mL, for example A PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 33.3 mg / mL ; Contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 (for example (i) A buffering agent having a pH of 5.5; and 0.01% to 0.015%, for example, 0.013 Contains a surfactant or polysorbate 20 present at a concentration of %(w / w).

[0391] In some embodiments, the formulation (e.g., the active ingredient formulation) is 30-35 mg / mL, for example A PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of 33.3 mg / mL ; Contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 (for example A buffer with a pH of 5.5) at a concentration of 70 mM to 75 mM, for example, 73.3 mM. Present carbohydrates or sucrose; and 0.01% to 0.015%, for example, 0.013% Contains a surfactant or polysorbate 20 present at a (w / w) concentration.

[0392] In some embodiments, the formulation (e.g., the active ingredient formulation) is at a concentration of 33.3 mg / mL Existing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules); histidyl at a concentration of 6.7 mM A buffer containing sucrose and having a pH of 5.5; sucrose present at a concentration of 73.3 mM. ; and also contains polysorbate 20 present at a concentration of 0.013% (w / w).

[0393] In some embodiments, the formulation is a lyophilized formulation. In certain embodiments, lyophilized The freeze-dried formulation is freeze-dried from the active ingredient formulation described herein. For example, 2-5 mL For example, 3-4 mL, for example 3.6 mL, the active ingredient formulation described herein in a container (e.g. Each vial can be filled and freeze-dried.

[0394] In certain embodiments, the formulation is a reconstituted formulation. For example, the reconstituted formulation is a protein By dissolving the lyophilized formulation in the diluent so that the chlorine is dispersed in the reconstituted formulation... It can be prepared by... In some embodiments, the lyophilized preparation is 0.5 mL to 2 mL, for example... It is then reconstituted with 1 mL of sterile water for injection or buffer solution. In certain embodiments, lyophilized formulations are used. For example, it can be reconstituted in a clinical setting with 1 mL of sterile water for injection.

[0395] In some embodiments, the formulation (e.g., the reconstituted formulation) contains a PD-1 inhibitor, LAG- 3 inhibitors, TIM-3 inhibitors, GITR agonists, SERD, CDK4 / 6 inhibitors, C XCR2 inhibitors, CSF-1 / 1R binders, c-MET inhibitors, TGF-β inhibitors, A2 aR agonist, IDO inhibitor, MEK inhibitor, IL-15 / IL-15RA complex, I The solution comprises an L-1β inhibitor or any combination thereof, and a buffer.

[0396] In some embodiments, the formulation (e.g., the reconstituted formulation) is 20 mg / mL to 200 mg g / mL, for example, 50 mg / mL to 150 mg / mL, 80 mg / mL to 120 mg / mL L or 90 mg / mL to 110 mg / mL, for example 50 mg / mL, 60 mg / mL, 7 0mg / mL, 80mg / mL, 90mg / mL, 100mg / mL, 110mg / mL , 120mg / mL, 130mg / mL, 140mg / mL, 150mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, or 200 mg / Contains a PD-1 inhibitor (e.g., an anti-PD-1 antibody molecule) present at a concentration of mL. In terms of administration, the PD-1 inhibitor (e.g., anti-PD-1 antibody molecule) is administered in doses of 80-120 mg. It exists at a concentration of / mL, for example, 100 mg / mL.

[0397] In some embodiments, the formulation (e.g., the reconstituted formulation) contains histidine (e.g., histidine). The buffer contains a thidine buffer. In certain embodiments, the buffer contains a thidine buffer (e.g., histidine buffer). The dilution ratio of the Zin buffer is 5mM to 100mM, for example, 10mM to 50mM, 15mM to 25mM. For example, 5mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70 It is present at concentrations of mM, 80 mM, 90 mM, or 100 mM. In some embodiments, The buffer (e.g., histidine buffer) should be at a concentration of 15 mM to 25 mM, for example, 20 mM. It exists. In other embodiments, a buffer (e.g., histidine buffer) is used, for example, 4-7. For example, having a pH of 5 to 6, for instance 5, 5.5, or 6. In some embodiments, a buffering agent (For example, histidine buffer) has a pH of 5-6, for example, 5.5. Specific implementation In this state, the buffering agent contains histidine at a concentration of 15 mM to 25 mM (for example, 20 mM). It contains and has a pH of 5-6 (for example, 5.5).

[0398] In some embodiments, the formulation (e.g., the reconstituted formulation) is 80-120 mg / mL. For example, a PD-1 inhibitor present at a concentration of 100 mg / mL (e.g., an anti-PD-1 antibody molecule) ); and containing histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 It includes a buffer having a pH of (for example, 5.5).

[0399] In some embodiments, the formulation (e.g., a reconstituted formulation) further comprises carbohydrates. In some embodiments, the carbohydrate is sucrose. In some embodiments, A substance (for example, sucrose) is 100 mM to 500 mM, for example, 150 mM to 400 mM. , 175mM~300mM or 200mM~250mM, for example 150mM, 160mM , 170mM, 180mM, 190mM, 200mM, 210mM, 220mM, 230 mM, 240 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM or It exists at a concentration of 300 mM. In some embodiments, the formulation is 200 mM to 250 mM. It contains carbohydrates or sucrose present at a concentration of M, for example, 220 mM.

[0400] In some embodiments, the formulation (e.g., the reconstituted formulation) is 80-120 mg / mL. For example, a PD-1 inhibitor present at a concentration of 100 mg / mL (e.g., an anti-PD-1 antibody molecule) ); containing histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 (e.g. For example, a buffer with a pH of 5.5); and 200 mM to 250 mM, for example, 220 mM It contains carbohydrates or sucrose present at a concentration of [value].

[0401] In some embodiments, the formulation (e.g., a reconstituted formulation) further comprises a surfactant. In certain embodiments, the surfactant is polysorbate 20. In some embodiments, In this case, the surfactant or polysorbate 20 is present in an amount of 0.01% to 0.1% (w / w), for example 0.02%~0.08%, 0.025%~0.06%, or 0.03%~0.05% (w / w), for example 0.01%, 0.025%, 0.03%, 0.04%, 0.05%, 0. It is present at concentrations of 0.6%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation contains 0.03% to 0.05%, for example, 0.04% (w / Contains a surfactant or polysorbate 20 present at the concentration of w).

[0402] In some embodiments, the formulation (e.g., the reconstituted formulation) is 80-120 mg / mL. For example, a PD-1 inhibitor present at a concentration of 100 mg / mL (e.g., an anti-PD-1 antibody molecule) ); containing histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 (e.g. For example, a buffer having a pH of 5.5); and 0.03% to 0.05%, for example, 0.04% Contains a surfactant or polysorbate 20 present at a (w / w) concentration.

[0403] In some embodiments, the formulation (e.g., the reconstituted formulation) is 80-120 mg / mL. For example, a PD-1 inhibitor present at a concentration of 100 mg / mL (e.g., an anti-PD-1 antibody molecule) ); and containing histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and 5 to 6 A buffer with a pH of (for example, 5.5); 200 mM to 250 mM, for example, 220 mM Carbohydrates or sucrose present at concentrations of 0.03% to 0.05%, for example, 0.0 Contains a surfactant or polysorbate 20 present at a concentration of 4% (w / w).

[0404] In some embodiments, the formulation (e.g., the reconstituted formulation) is at a concentration of 100 mg / mL Existing PD-1 inhibitors (e.g., anti-PD-1 antibody molecules); and histogenic drugs at a concentration of 6.7 mM A buffer containing thidine and having a pH of 5.5; sucrose present at a concentration of 220 mM. It contains S and polysorbate 20 present at a concentration of 0.04% (w / w).

[0405] In some embodiments, the formulation contains at least 1 mL of an extractable volume (for example, less than The reconstituted preparation contains at least 1.5 mL, 2 mL, 2.5 mL, or 3 mL of the reconstituted preparation. It is reconfigured so that it can be withdrawn from a container (e.g., a vial). Specific Embodiments In this process, the formulation is reconstituted in the clinical setting and / or removed from the container (e.g., vial). It is taken out. In certain embodiments, the formulation (e.g., the reconstituted formulation) is administered to the patient. For example, within one hour before starting (for example, within 45 minutes, 30 minutes, or 15 minutes), put the contents into the infusion bag. It will be injected.

[0406] In certain embodiments, the formulation is a liquid formulation. The agent is prepared by diluting the active ingredient formulation described herein. For example, The formulation contains 10-30 mg / mL of one or more excipients (e.g., concentrated excipients). For example, it can be diluted with a solution of 25 mg / mL. In some embodiments, the solution is Containing one, two, or all of stidine, sucrose, or polysorbate 20. Specific implementation In terms of form, the solution contains the same excipients as the active ingredient formulation. Exemplary excipients include amino acids. Acids (e.g., histidine), carbohydrates (e.g., sucrose), or surfactants (e.g., Examples include, but are not limited to, polysorbate 20). In certain embodiments, The liquid formulation is not a lyophilized formulation that is reconstituted. In other embodiments, the liquid formulation is It is a lyophilized formulation that is reconstituted. In some embodiments, the formulation is stored as a liquid. In other embodiments, the formulation is prepared as a liquid and then frozen, for example, before storage. It is dried by boiling or spray drying.

[0407] In some embodiments, the formulation (e.g., liquid formulation) is 5 mg / mL to 50 mg / m². L, for example, 10 mg / mL to 40 mg / mL, 15 mg / mL to 35 mg / mL, or 20 mg / mL to 30 mg / mL, for example 5 mg / mL, 10 mg / mL, 15 mg / mL, 20mg / mL, 25mg / mL, 30mg / mL, 35mg / mL, 40mg / mL, PD-1 inhibitors present at concentrations of 45 mg / mL or 50 mg / mL (e.g., anti-PD- Contains 1 antibody molecule. In certain embodiments, a PD-1 inhibitor (e.g., anti-PD-1 inhibitor) is also included. Body molecules are present at concentrations of 20-30 mg / mL, for example, 25 mg / mL.

[0408] In some embodiments, the formulation (e.g., liquid formulation) contains histidine (e.g., histidine The buffer contains a din buffer. In certain embodiments, the buffer contains a din buffer (e.g., histidine). The buffer solution can be 5mM to 100mM, for example, 10mM to 50mM, 15mM to 25mM, For example, 5mM, 10mM, 20mM, 30mM, 40mM, 50mM, 60mM, 70mM It is present at concentrations of M, 80mM, 90mM, or 100mM. In some embodiments, it is slow The buffer (e.g., histidine buffer) is prepared at a concentration of 15 mM to 25 mM, for example, 20 mM. It is present. In other embodiments, the buffer (e.g., histidine buffer) is 4-7, for example The pH is 5 to 6, for example, 5, 5.5 or 6. In some embodiments, a buffer is used. For example, the histidine buffer has a pH of 5-6, for example, 5.5. Specific Embodiments In this context, the buffer contains histidine at a concentration of 15 mM to 25 mM (for example, 20 mM). It also has a pH of 5-6 (for example, 5.5).

[0409] In some embodiments, the formulation (e.g., liquid formulation) contains 20-30 mg / mL, for example PD-1 inhibitors present at a concentration of 25 mg / mL (e.g., anti-PD-1 antibody molecules); and It contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and also contains 5 to 6 (for example) The buffer contains a pH of 5.5).

[0410] In some embodiments, the formulation (e.g., a liquid formulation) further comprises carbohydrates. In some embodiments, the carbohydrate is sucrose. In some embodiments, the carbohydrate (For example, sucrose) is 100 mM to 500 mM, for example, 150 mM to 400 mM. 175mM~300mM or 200mM~250mM, for example 150mM, 160mM, 170mM, 180mM, 190mM, 200mM, 210mM, 220mM, 230m M, 240mM, 250mM, 260mM, 270mM, 280mM, 290mM or 3 It exists at a concentration of 00 mM. In some embodiments, the formulation is 200 mM to 250 mM For example, it contains carbohydrates or sucrose present at a concentration of 220 mM.

[0411] In some embodiments, the formulation (e.g., liquid formulation) contains 20-30 mg / mL, for example PD-1 inhibitors present at a concentration of 25 mg / mL (e.g., anti-PD-1 antibody molecules); and It contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and also contains 5 to 6 (for example) , a buffer having a pH of 5.5); and a 200 mM to 250 mM, for example, 220 mM Contains carbohydrates or sucrose present in concentration.

[0412] In some embodiments, the formulation (e.g., a liquid formulation) further comprises a surfactant. In some embodiments, the surfactant is polysorbate 20. Furthermore, the surfactant or polysorbate 20 is present in an amount of 0.01% to 0.1% (w / w), for example. 0.02%~0.08%, 0.025%~0.06%, or 0.03%~0.05% (w / w), for example 0.01%, 0.025%, 0.03%, 0.04%, 0.05%, 0.0 It is present in concentrations of 6%, 0.07%, 0.08%, 0.09%, or 0.1% (w / w). In some embodiments, the formulation is 0.03% to 0.05%, for example, 0.04% (w / w). It contains a surfactant or polysorbate 20 present at the concentration of ).

[0413] In some embodiments, the formulation (e.g., liquid formulation) contains 20-30 mg / mL, for example PD-1 inhibitors present at a concentration of 25 mg / mL (e.g., anti-PD-1 antibody molecules); and It contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and also contains 5 to 6 (for example) a buffer having a pH of 5.5); and 0.03% to 0.05%, for example 0.04% ( It contains a surfactant or polysorbate 20 present at a concentration of w / w.

[0414] In some embodiments, the formulation (e.g., liquid formulation) contains 20-30 mg / mL, for example PD-1 inhibitors present at a concentration of 25 mg / mL (e.g., anti-PD-1 antibody molecules); and It contains histidine at a concentration of 6 mM to 7 mM (for example, 6.7 mM), and also contains 5 to 6 (for example) 5.5) A buffering agent having a pH of 200 mM to 250 mM, for example, 220 mM. Carbohydrates or sucrose present in the food; and 0.03% to 0.05%, for example, 0.04% ( It contains a surfactant or polysorbate 20 present at a concentration of w / w.

[0415] In some embodiments, the formulation (e.g., liquid formulation) is present at a concentration of 25 mg / mL. PD-1 inhibitors (e.g., anti-PD-1 antibody molecules); and histidine at a concentration of 6.7 mM A buffer containing sucrose and having a pH of 5.5; sucrose present at a concentration of 220 mM; It also contains polysorbate 20 present at a concentration of 0.04% (w / w).

[0416] In certain embodiments, 1 mL to 10 mL (for example, 2 mL to 8 mL, 3 mL to 7 mL) L or 4mL-5mL, for example 3mL, 4mL, 4.3mL, 4.5mL, 5mL or 6mL A liquid formulation (mL) is filled into each container (e.g., vial). In another embodiment, The liquid formulation contains at least 2 mL (for example, at least 3 mL, and at least) of an extractable volume. A liquid preparation of 4 mL or at least 5 mL is drawn out from each container (e.g., vial). The liquid formulation is filled into a container (e.g., a vial) to obtain the desired product. In certain embodiments, liquid formulations are obtained. It is diluted from the active ingredient and / or withdrawn from the container (e.g., vial) in the clinical setting. In certain embodiments, the formulation (e.g., a liquid formulation) begins to be injected into the patient. Inject into the injection bag within the previous hour (for example, 45 minutes, 30 minutes, or 15 minutes). It can be done.

[0417] The formulations described herein may be stored in containers. The containers used for either purpose are, for example, vials and optionally stoppers, caps. It may include or both. In certain embodiments, the vial is a glass vial, for example It is a 6R white glass vial. In other embodiments, the stopper is a rubber stopper. For example, a gray rubber stopper. In another embodiment, the cap is a flip-off A cap, for example, an aluminum flip-off cap. In some embodiments, The container consists of a 6R white glass vial, a gray rubber stopper, and an aluminum flip-off cap. Includes a cap. In some embodiments, the container (e.g., vial) is a disposable container. In certain embodiments, the dose is 50 mg to 150 mg, for example, 80 mg to 120 mg. , 90mg~110mg, 100mg~120mg, 100mg~110mg, 110m g-120 mg or 110-130 mg of a PD-1 inhibitor (e.g., anti-PD-1 antibody) The molecule is present in the container (e.g., a vial).

[0418] Other exemplary buffering agents that may be used in the formulations described herein include argy Examples include, but are not limited to, nin buffer, citrate buffer, or phosphate buffer. Other exemplary carbohydrates that may be used in the formulations described herein include trehalose. Examples include rosin, mannitol, sorbitol, or combinations thereof. Not limited to, the formulations described herein include osmotic agents, such as sodium chloride and / or These are stabilizers, such as amino acids (e.g., glycine, arginine, methionine, or combinations thereof). It may also contain (combinations).

[0419] Therapeutic agents, such as inhibitors, antagonists, or binders, are various types known in the art. Although it may be administered by law, for many therapeutic applications, the preferred route / method of administration is static. This is done by intravenous injection or infusion. For example, the antibody molecule is administered intravenously at a rate of 20 mg / min, for example. Administer at a rate of 20-40 mg / min and typically 40 mg / min or higher, for approximately 35-440 mg / m 2Typically, approximately 70-310 mg / m² 2 And more typically around 110-130 mg / m 2 A dose can be reached. In the embodiment, the antibody molecule is administered by intravenous injection. Administer at a rate of less than 10 mg / min; preferably 5 mg / min or less, to a dose of approximately 1 to 100 mg. / m 2 Preferably about 5-50 mg / m² 2 , about 7~25mg / m 2 and more preferably about 10 mg / m² 2 This dose can be reached. As those skilled in the art will understand, the administration time The path and / or method may vary depending on the desired result. In certain embodiments, activation The combination includes implants, percutaneous patches, and microencapsulated delivery systems. It can be prepared with a carrier that prevents the rapid release of the compound, such as a controlled-release formulation. Ethyleneacetic acid Vinyl, polyanhydride, polyglycolic acid, collagen, polyorthoesters and polymilk Acids and other biodegradable and biocompatible polymers may be used. Many of the methods for preparing such formulations , patented or generally known to those skilled in the art. For example, Sustained a nd Controlled Release Drug Delivery System ems, JR Robinson, ed., Marcel Dekker, Inc., See New York, 1978.

[0420] In certain embodiments, the therapeutic agent or compound is, for example, an inert diluent or an assimilated agent. It can be administered orally with an edible carrier. The compound (and other components as needed) also , encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or It can be directly incorporated into the target diet. For oral therapeutic administration, the compound is formulated together with excipients. These include tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, and syrups that can be taken orally. It can be used in the form of a wafer or other similar material. The compounds of this disclosure may be administered by means other than parenteral administration. To do this, the compound is coated with a material that prevents its deactivation, or the compound is mixed with the compound It may be necessary to administer co-administer the therapeutic composition, even if it is a medical device known in the art. It may be permitted.

[0421] The medication regimen is adjusted to produce the optimal desired response (e.g., therapeutic response). For example, a single bolus may be administered, or several divided doses may be administered over time. The dosage may be reduced or increased proportionally according to the urgency of the treatment situation. This is possible. In particular, for ease of administration and uniformity of dosage, parenteral compositions may be prepared in dosage units. It is advantageous to formulate the drug in a specific form. The drug dosage unit form, as used herein, refers to the therapeutic form. This refers to a physically individual unit suitable as a unit dose of medication for the target of treatment. Each unit represents the desired treatment. It contains a predetermined amount of the active compound, calculated to produce a therapeutic effect, together with the necessary pharmaceutical carrier. The specifications relating to the dosage unit form of the present invention are (a) the unique properties of the active compound and The detailed therapeutic effect to be achieved, and (b) the activity to treat the individual's susceptibility It is influenced by and directly dependent on the inherent constraints of compound synthesis techniques.

[0422] An exemplary, non-limiting range of the therapeutic or prophylactic effective dose of the therapeutic agent is 0.1 to 30 mg / kg. Preferably, the dosage is 1 to 25 mg / kg. Dosage and treatment regimen of anti-PD-1 antibody molecule This can be determined by those skilled in the art. In certain embodiments, the anti-PD-1 antibody molecule is about 1 to 40 mg / kg, for example 1-30 mg / kg, for example approximately 5-25 mg / kg, approximately 10-20 mg g / kg, about 1~5mg / kg, 1~10mg / kg, 5~15mg / kg, 10~20 Administered by injection at doses of mg / kg, 15-25 mg / kg, or approximately 3 mg / kg (for example, It is administered subcutaneously or intravenously. The administration schedule is, for example, once a week to every two, three, or four weeks. It can vary once in between. In one embodiment, the anti-PD-1 antibody molecule is administered approximately once every week. It is administered at a dose of 0-20 mg / kg.

[0423] As another example, the non-limiting range for the therapeutic or prophylactic effective dose of an antibody molecule is 200-500 mg. , more preferably 300-400 mg / kg. Dosage of anti-PD-1 antibody molecule and treatment The treatment regimen can be determined by those skilled in the art. In certain embodiments, the anti-PD-1 antibody molecule is Approximately 200mg to 500mg, for example, approximately 250mg to 450mg, or approximately 300mg to 400mg. g, approximately 250mg-350mg, approximately 350mg-450mg, or approximately 300mg or approximately Administered by injection (e.g., subcutaneously or intravenously) in a dose of 400 mg (e.g., a flat dose) ) is administered. The administration schedule (e.g., flat administration schedule) is, for example, weekly. The frequency may vary from once every 1 to 2, 3, 4, 5, or 6 weeks. In one embodiment, anti-PD-1 anti Body molecules are administered at a dose of approximately 300 mg to 400 mg once every three weeks or once every four weeks. In one embodiment, the anti-PD-1 antibody molecule is administered once every three weeks at a dose starting from approximately 300 mg. It is administered. In one embodiment, the anti-PD-1 antibody molecule is administered in doses starting from about 400 mg. It is administered once a week. In one embodiment, the anti-PD-1 antibody molecule is administered in doses of approximately 300 mg. It is administered once every four weeks at this dose. In one embodiment, the anti-PD-1 antibody molecule is approximately 40 It is administered once every three weeks, starting at a dose of 0 mg. It is intended to be constrained by theory. However, in some embodiments, a flat dose or fixed dose is used, for example, in drug delivery. This can be beneficial to patients because it saves money and reduces dispensing errors.

[0424] In some embodiments, the clearance (CL) of the anti-PD-1 antibody molecule is approximately 6-16 mL / h, for example, about 7-15 mL / h, about 8-14 mL / h, about 9-12 mL / h, or about 10-11 mL / h, for example, approximately 8.9 mL / h, 10.9 mL / h, or 13.2 mL / h That is the case.

[0425] In some embodiments, the body weight exponential term for the anti-PD-1 antibody molecule relative to CL is approximately 0. 4 to 0.7, approximately 0.5 to 0.6 or 0.7 or less, for example, 0.6 or less or approximately 0.54. .

[0426] In some embodiments, the steady-state volume of distribution (Vss) of the anti-PD-1 antibody molecule is approximately 5 ~10V, for example, about 6~9V, about 7~8V, or about 6.5~7.5V, for example, about 7.2V be.

[0427] In some embodiments, the half-life of the anti-PD-1 antibody molecule is approximately 10 to 30 days, for example, approximately 15-25 days, approximately 17-22 days, approximately 19-24 days, or approximately 18-22 days, for example, approximately 20 days. be.

[0428] In some embodiments, the Cmin of the anti-PD-1 antibody molecule (for example, in a patient weighing 80 kg) Regarding this, at least about 0.4 μg / mL, for example, at least about 3.6 μg / mL, for example For example, approximately 20-50 μg / mL, or approximately 22-42 μg / mL, or approximately 26-47 μg / mL. , about 22-26μg / mL, about 42-47μg / mL, about 25-35μg / mL, about 32 ~38 μg / mL, for example, about 31 μg / mL or about 35 μg / mL. In one embodiment In this case, Cmin received an anti-PD-1 antibody molecule at a dose of approximately 400 mg once every four weeks. This is determined in the patient. In another embodiment, Cmin is an anti-PD-1 antibody molecule Determined in patients receiving a dose of approximately 300 mg once every three weeks. (Some embodiments) In a particular embodiment, Cmin is used, for example, in an SEB exovivo assay. When determined based on IL-2 changes, the EC50 of the anti-PD-1 antibody molecule is at least approximately 50 times higher, for example, at least about 60 times, 65 times, 70 times, 75 times, 80 times, 85 times, 9 0 times, 95 times, or 100 times, for example, at least about 77 times higher. In other embodiments, C min is, for example, determined based on IL-2 changes in an SEB exovivo assay. At least 5 times higher than the EC90 of the anti-PD-1 antibody molecule, for example, at least 6 or 7 times higher. It's 8 times, 9 times, or 10 times higher, for example, at least about 8.6 times higher.

[0429] Antibody molecules are administered intravenously at doses exceeding 20 mg / min, for example, 20-40 mg / min and typical doses. It should be administered at a rate of 40 mg / min or more, at a rate of approximately 35-440 mg / m². 2 Typically about 70 ~310 mg / m² 2 And more typically, about 110-130 mg / m² 2 Reaching the dose This can be achieved. In the embodiment, approximately 110-130 mg / m² 2 The infusion rate is approximately 3 mg / kg This level is achieved. In other embodiments, the antibody molecule is administered intravenously at a dose of 10 mg / Administer at a rate of less than one minute, for example, 5 mg / min or less, to approximately 1-100 mg / m². 2 For example, about 5 ~50mg / m 2 , about 7~25mg / m 2 Or approximately 10 mg / m² 2 It is possible to reach the dose In some embodiments, the antibody is injected over a period of approximately 30 minutes. It should be noted that the values ​​may vary depending on the type and severity of the condition being treated. Yes. Furthermore, for any specific subject, the specific dosage regimen changes over time. The individual needs and the professional judgment of the administerer or monitor of the composition are adjusted accordingly. It must be done that the dosage range shown in the specification is merely illustrative and not applicable to the patent claims. It should be understood that there is no intention to limit the scope or implementation of the composition.

[0430] The pharmaceutical composition of the present invention contains a "therapeutic effective amount" or "preventive effective amount" of the antibody or antibody portion of the present invention. This may include "effective dose." "Therapeutic dose" refers to the amount and duration of medication required to achieve the desired therapeutic outcome. This refers to the effective amount to achieve that. The therapeutically effective amount of modified antibody or antibody fragment is the amount of the individual's disease Condition, age, sex, and weight, as well as the antibody or antibody portion thereof, which elicits the desired response in the individual. It may vary depending on factors such as ability. The therapeutically effective dose is any modified antibody or antibody fragment. The therapeutically beneficial effects outweigh any toxicity or adverse effects. The "therapeutally effective dosage" is: Preferably, measurable parameters, such as tumor growth rate, are reduced compared to untreated subjects. Both are approximately 20%, more preferably at least approximately 40%, and even more preferably at least approximately 6 It inhibits by 0% and more preferably by at least about 80%. The compound has measurable parameters. For example, the ability to inhibit cancer is evaluated in animal model systems, which can be used to predict efficacy in human tumors. It can be valued. Instead, this property of the composition is known to those skilled in the art as the inhibitory ability of the compound. This can be evaluated by examining such inhibition in vitro using assays.

[0431] "Preventive effective dose" is the amount and duration of medication required to achieve the desired preventive outcome. This refers to the amount that is effective for [doing something]. Typically, a prophylactic dose is used in a subject prior to or after the onset of disease. Because it is used in the early stages of treatment, the prophylactic effective dose may be less than the therapeutic effective dose.

[0432] LUTATHERA (Lutetium Lu 177 doatete) is a radiolabeled solubility It is a matostatin analog. The proto-lutetium Lu-177 dotathete is a radionuclide. Covalent chelator 1,4,7,10-tetraazacyclododecane-1,4,7 It is a cyclic peptide linked to 10-tetraacetic acid.

[0433] Lutetium Lu 177 dotathete is lutetium (Lu177)-N-[(4, 7,10-Tricarboxymethyl-1,4,7,10-Tetraazacyclododeca-1-i [L)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptose Fanyl-L-lysyl-L-threonyl-L-cysteinyl-L-threonine-cyclic (2 -7) Described as a disulfide. Its molecular weight is 1609.6 daltons, and its structural formula is... The following applies: [ka]

[0434] LUTATHERA (Lutetium Lu 177 doate) 370 MBq / mL The (10 mCi / mL) injection is a sterile, clear, colorless to pale yellow solution for intravenous use. Yes. Each single-dose vial contains acetic acid (0.48 mg / mL) and sodium acetate (0.66 mg / mL). (mg / mL), gentisic acid (0.63 mg / mL), sodium hydroxide (0.65 mg ( / mL), ascorbic acid (2.8 mg / mL), diethylenetriaminepentaacetic acid (0.0 Add 5 mg / mL, sodium chloride (6.85 mg / mL), and sterile water for injection (up to 1 mL). It contains ( ). The pH range of the solution is 4.5 to 6.

[0435] Lutetium Lu 177 doate at 370 MBq / mL (10 mCi / ml) The LUTATHERA injection contained in this product delivers 7.4 GBq (200 mCi) ± 10% at the time of injection. A single dose vial of 30 mL of colorless Type I glass containing lutetium Lu 177 doate. Sterile, preservative-free, and clear, colorless to pale yellow, clear, colorless, and clear for intravenous use supplied at IAL. This is a colored solution (NDC#69488-003-01). The total volume of solution in the vial is Adjust to 20.5 mL to 25 mL to provide 7.4 GBq (200 mCi) of radioactivity. It will be done.

[0436] The product vials are stored in a sealed plastic container (NDC#69488-003-01). It is contained in a lead-shielded container. The product is in a Type A package (NDC#69488-003-7 It is transported in 0).

[0437] Store at temperatures below 25°C (77°F).

[0438] The validity period is 72 hours. Dispose of it properly after 72 hours.

[0439] kit The combinations of therapeutic agents disclosed herein may be provided in a kit. Generally, the therapeutic agent is provided in vials or containers. Depending on the circumstances, the therapeutic agent may be in liquid or dry form (e.g. The kit may be in a freeze-dried form. It may include two or more (for example, three, four, five, or all). In some embodiments, kits The drug further contains a pharmaceutically acceptable diluent. The therapeutic agent is the same or a different formulation (for example) The kit may be provided as a mixture or in a kit (in separate containers). It may contain a fixed amount of the therapeutic agent to provide one or more doses. A fixed amount for multiple doses. If provided, the dose may be uniform or different. Various dosing regimens may be used as appropriate. The dosage may be gradually increased or decreased. The dosage of the therapeutic agents in the combination is independent and uniform. or may differ. This kit includes instructions for use; other reagents, such as labeling or therapeutic agents, may be used. Alternatively, agents useful for chelation or coupling with therapeutic agents or Radiation protective compositions; apparatus or other materials for preparing antibodies for administration; pharmaceutically acceptable A possible carrier; and one or more other elements including a device or other material for administration to the subject. It may include. [Examples]

[0440] The advanced therapeutic effects of the combination of PRRT and IO agents in the treatment of NET tumors are, As described illustratively in Example 2, and as described in Example 3 In the clinical trial of the product, the test drug was used as exemplified in Example 1. This can be demonstrated. The following NET tumors are small cell lung cancer (SCLC) or pulmonary NET (pN). It could be ET. Clinical trials are, 177 Lu-DOTA 0 -Tyr 3 - Octoreote The combination of IO treatment agents is safe and acceptable, and SCLC or pNET In maintenance therapy for patients who have the condition and have not experienced disease progression after first-line platinum-based chemotherapy. This demonstrates that it provides a benefit to PFS compared to observation alone.

[0441] Example 1: Test Drug Information 177 Lu-DOTA 0 -Tyr 3 - Octoreote 177 Lu-DOTA 0 -Tyr 3 - Octreotete is supplied as a ready-made product. This is a radiopharmaceutical solution for injection. No product handling is required in a clinical setting. 177Lu-DOTA0-Tyr3-Octreotete is used in centralized GMP facilities. It is manufactured using a special process and undergoes quality control testing before being supplied to the market.

[0442] The product is manufactured and supplied to the clinical setting in single-dose vials. One vial contains 7.4G of compound solution in 22-25 mL of formulation solution during calibration (injection). Bq(200mCi) 177 Lu-DOTA 0 -Tyr 3 - Contains octreotete The variability of the volume depends on the time between the calibration date and the manufacturing date. The product is aggregated G After being manufactured at the MP facility, the products are transported and calibrated for use at 24 or 48 hours. The dose calibration time depends on the distance from the manufacturing facility to the clinical site. The amount of energy, 7.4 GBq (±10%), is determined at the time of injection.

[0443] The physicochemical properties of each dose are listed in the table below.

[0444] [Table 35]

[0445] The test drug is for a 74 GBq batch size (2 Ci batch size), 177 LuC The l3 solution contains approximately 74 GBq of HCl and is generated in less than 15 minutes at a temperature of approximately 90-98°C. DOTA-Tyr, used for radioactive labeling, is a solution totaling approximately 5.5 mL. 3 -O Ctreotate (approximately 2 mg) solution and antioxidant (and radioactive degradation) Stabilizer for chemical reaction (i.e., gentisinic acid, approximately 157 mg) and buffer system (i.e., acetate buffer system) It is mixed with a reaction buffer solution containing [the substance].

[0446] The synthesis involves a synthetic module containing a fluid pathway (piping), reactor vial, and sealed reagent vial. This procedure is performed using a single-use, disposable kit cassette located at the front of the rudle.

[0447] The resulting mother liquor is mixed with a chelating agent (i.e., DTPA), an antioxidant (i.e., ascorbic acid), and water. Dilute with a solution containing sodium oxide and sodium chloride, then pass through a 0.2 μm filter. Sterilize and filter to obtain the prepared solution as described above, with a pH of 5.2-5.3. Finally, Dispense the solution into sterile vials with a volume of 20.5–25.0 mL. Attach a stopper to the vial. The ial is sealed in a lead container for protective shielding.

[0448] 177 Lu-DOTA0 -Tyr 3 - Treatment with octreotate should be administered at intervals of 8 ± 1 weeks. in 177 Lu-DOTA 0 -Tyr 3 - Equally between each of the four doses of octreotate The divided dosing will result in a cumulative dose of 29.6 GBq (800 mCi).

[0449] IO treatment agent (antibody) explanation

[0450] [Table 36]

[0451] preparation Take the required volume of antibody solution and transfer it to a container for intravenous injection.

[0452] Antibody solution: 0.9% sodium chloride injection, USP or 5% dextrose injection, U Dilute with one of the SPs and prepare the injection solution at a final concentration in the range of 1 mg / mL to 10 mg / mL. Prepare. For dilution, add the antibody injection to an empty injection container, followed by NS or D5W. The antibody injection can be diluted by adding or by adding an appropriate volume of N in a pre-filled injection container. It can be directly applied to S or D5W.

[0453] Mix the diluted solution by gently inverting the container. Do not shake.

[0454] Storage of injection fluid The product does not contain preservatives. After preparation, the antibody injection solution is... Keep at room temperature for 4 hours or less from the time of preparation (this refers to the storage of the injectable solution in the IV container at room temperature and (including time for administering the infusion), or Keep refrigerated at 2°C to 8°C (36°F to 46°F) for 24 hours or less from the time of injection solution preparation. Store in one of the following ways. Do not freeze.

[0455] Example 2: Administration of test drug 177 Lu-DOTA 0 -Tyr 3 - Octoreote 177 Lu-DOTA 0 -Tyr 3 - Octreotate is administered every 8 weeks. 1 77 Lu-DOTA 0 -Tyr 3 - The first dose of octreotate is the first dose of the antibody. It is administered for two weeks after the initial dose. Each dose is infused over 30 minutes. 177 Lu-DOTA 0 -Tyr 3 -An intravenous bolus of antiemetic is administered on the day of octreotate infusion (suggestion) The available options are: ondansetron (8mg), granisetron (3mg), or tropisetron. Ron (5mg). 177 Lu-DOTA 0 -Tyr 3 - Octreotate administration is available. It may be done one day earlier or up to one week later due to bad weather, conflict or similar reasons. Prednisone is used as a prophylactic antiemetic due to its potential negative effects on anti-PD-1 therapy. This should be avoided. If nausea or vomiting occurs despite the use of the aforementioned antiemetic, the patient The patient may be treated with other antiemetic prescriptions at the discretion of the attending physician.

[0456] Simultaneous infusion of amino acids resulted in a significant reduction (47%) in the average radiation dose to the kidneys. Therefore, the combination of amino acids 177 Lu-DOTA 0 -Tyr 3 - Each of the Octreotetes It is given along with the dosage. Amino acid solution and177 Lu-DOTA 0 -Tyr 3 - Octre Otate is administered concurrently via peripheral intravenous infusion.

[0457] [Table 37]

[0458] IO treatment agent The antibody is administered once every two weeks until disease progression, patient withdrawal, or toxicity occurs. It is administered intravenously, first in combination tests. Before the next compound is administered. Wait 30 minutes (regardless of the route of administration). To ensure that the entire dose is administered, The intravenous line is rinsed with an appropriate amount of diluent (15-20 ml) at the end of the injection. Antibody administration. It may be done one day earlier or up to one week later due to holidays, bad weather, disputes or similar reasons. Obtain. Next, adjust the timing of subsequent administrations to maintain a 14-day interval. Antibody dose The selection is made for each patient or group, as outlined in the section on drug administration in the clinical protocol. It should be allocated.

[0459] General recommendations for evaluating toxicity and dose postponement / modification Any patient treated under this protocol can be evaluated for toxicity. Toxicity is N The drug will be evaluated according to the Common Toxicity Criteria for Adverse Events (CTCAE), version 4.03. Delay in administration or Dosage changes should be made according to the system exhibiting the highest degree of toxicity. If a dose reduction is necessary, the dose will not be gradually increased again. (Delayed administration and changes in administration) This is done using the following recommendations.

[0460] If the observed adverse event is attributable to only one of the study drugs, the principal investigator may, at their discretion, allow the patient to be discharged. , the ability to retain the test drug while continuing to receive a drug unrelated to the observed AE, or The dosage can be changed independently.

[0461] 177 Lu-DOTA 0 -Tyr 3 - Changes in the dosage of octreotate are shown in the table below. It is permitted according to the following.

[0462] [Table 38]

[0463] Regarding antibodies, dose changes are not permitted.

[0464] Example 2: Combination of Lutathera and antibody as IO treatment agent I / II Phase 1 clinical trial Main purpose The primary objective of the Phase I portion of the study is to treat small cell lung cancer or advanced or inoperable Grade I lung cancer. ~II In patients with pulmonary NETs, ​​combination therapy with anti-PD-1 checkpoint inhibitor antibodies When given together, 177 Lu-DOTA 0 -Tyr 3 - Octreotete's RP2 The task is to determine D.

[0465] The primary objective of the Phase II portion of the trial was to observe the maintenance therapy as a form of observation. 177 Lu-DO TA 0 -Tyr 3 - After receiving combination therapy with octreotate and antibodies, platinum-based In patients with ES-SCLC who had not progressed to first-line treatment with cytosis therapy, P The goal is to compare the feasibility studies (FS).

[0466] Secondary purpose Combined with antibodies 177 Lu-DOTA 0 -Tyr 3 - Octreotate safety Characterizing the rofile. [Applicable to both Phase 1 and Phase 2 portions]

[0467] In patients whose disease has not progressed before initiating combination therapy: [Applicable to the Phase 2 portion] ] 〇 177 Lu-DOTA 0 -Tyr 3 - DCR after treatment with octreotate and antibody And evaluate the ORR. ○ Evaluate the operating system. Observed in the NETSPOT(registered trademark) PET scan obtained during Cycle 2 on Day 1. To evaluate whether the metabolic response predicts the response to the test treatment.

[0468] Inclusion Criteria (Phase I) The patient has cytologically or histologically confirmed relapsed or refractory advanced small cell lung cancer. ES-SCLC), or ES-SCLC that has not progressed after first-line medical therapy, or progressive Alternatively, the patient must have an inoperable grade I-II pulmonary NET.

[0469] NETSPOT (registered trademark) is equivalent to or higher than that found in normal liver tissue. Patients with tumor tissue uptake during PET (grade ≥ 2) would likely be eligible. At the discretion of the mentor, the tumor was found to have a lower uptake level than the liver in NETSPOT(registered trademark) PET. Patients with SCLC that have [specific characteristics] may be eligible for the trial.

[0470] Patients have a smaller size, >20mm with conventional techniques and >10mm with spiral CT scans. As at least one lesion that can be accurately measured in one dimension (the longest diameter recorded) The patient must have a measurable disease according to the defined RECIST criteria. For information on the evaluation of possible diseases, please refer to Section 7.1.2.

[0471] The toxicity of the previous therapy was harmless, except for alopecia and grade 2, and previous platinum therapy-related neuropathy. Unless it is restored to Grade 1 or lower according to the Common Terminology Criteria for Events (CTCAE) version 4.03 No.

[0472] Prior radiotherapy or radiosurgery (prophylactic cranial and / or thoracic radiation) (including) must be completed at least two weeks prior to randomization.

[0473] ECOG performance status from 0 to 1.

[0474] Sufficient organ and bone marrow function (hemoglobin > 9 g / dL; absolute neutrophil count > 1.5 × 10⁻¹⁴) 9 / L; Platelet count>100×10 9 / L;Serum bilirubin <2 × ULN;Alanine amino acid Lansferase (ALT) and aspartate aminotransferase (AST) 2.5 × ULN or <5 × ULN in the case of liver tumor metastasis, calculated creatinine clearance (Rating > 50 mL / min).

[0475] At least three months on average life expectancy.

[0476] Age > 18.

[0477] Inclusion Criteria (Phase II) The patient must have cytologically or histologically confirmed ES-SCLC. Furthermore, the disease must not have progressed after first-line platinum-based chemotherapy prior to randomization.

[0478] NETSPOT (registered trademark) is equivalent to or higher than that found in normal liver tissue. Patients with tumor tissue uptake during PET (grade ≥ 2) would likely be eligible. NETSP OT(registered trademark)PET is recommended to be obtained before starting chemotherapy, NETSPOT® PET acquired during or after the completion of chemotherapy is screened It could be used for the purpose of [unclear].

[0479] Patients have a smaller size, >20mm with conventional techniques and >10mm with spiral CT scans. As at least one lesion that can be accurately measured in one dimension (the longest diameter recorded) The patient must have a measurable disease according to the defined RECIST criteria. For information on the evaluation of possible diseases, please refer to Section 7.1.2.

[0480] The toxicity of the previous therapy was harmless, except for alopecia and grade 2, and previous platinum therapy-related neuropathy. Unless it is restored to Grade 1 or lower according to the Common Terminology Criteria for Events (CTCAE) version 4.03 No.

[0481] Prior radiotherapy or radiosurgery (prophylactic cranial and / or thoracic radiation) (including) must be completed at least two weeks prior to randomization.

[0482] For patients who have not received radiation therapy after chemotherapy, randomization is performed on the last chemotherapy regimen. The procedure must be performed within 6 weeks of randomization. The experimental procedure must be performed within 2 weeks of randomization. It must be initiated. Radiotherapy after chemotherapy (prophylactic cranial radiation and / or For patients receiving (including thoracic radiation therapy), randomization is applied to the last chemotherapy cycle. It must be performed within 9 weeks, but at least 2 weeks after the completion of radiation therapy. , 177 Lu-DOTA 0 -Tyr 3 - The first dose of octreotate is administered during 8 minutes of radiotherapy. It cannot be given within a week.

[0483] ECOG performance status from 0 to 1.

[0484] Sufficient organ and bone marrow function (hemoglobin > 9 g / dL; absolute neutrophil count > 1.5 × 10⁻¹⁴) 9 / L; Platelet count>100×10 9 / L;Serum bilirubin <2 × ULN;Alanine amino acid Lansferase (ALT) and aspartate aminotransferase (AST) 2.5 × ULN or <5 × ULN in the case of liver tumor metastasis, calculated creatinine clearance (Rating > 50 mL / min).

[0485] He has at least three months to live.

[0486] Age > 18.

[0487] Treatment plan Treatment dosage and administration Phase I Dose-limiting toxicity (DLT) DLT is calculated from the first dose of the study treatment (Day 1, Cycle 1) to the last day of the cycle (Day 57). Any toxicity occurring up to day (day) that is not attributable to the disease under investigation or a disease-related process. It is defined as follows. To be considered a DLT, it must meet the NCI Common Toxicity Criteria for Adverse Events (CTCAE). The test drug must be related to the test drug while meeting one of the following criteria in accordance with version 4.03. Not applicable (Attributes: likely relevant, highly likely relevant, definitely relevant): ●Toxicity grade 2 related to platelets and any other grade 3 or 4 toxicity, ○ Grade 3 diarrhea, nausea, or vomiting, if controllable with supportive care. ○Managed by the presence or absence of systemic corticosteroid therapy and / or hormone replacement therapy, patient This ruled out asymptomatic grade 3 endocrine disorders. ● Despite optimal medical treatment and a delay of >21 days in treatment, prolonged (>21 days) non-hematological Grade adverse events ● Any other toxicity: ○ Worse than baseline, described, clinically relevant and / or unacceptable, and If the principal investigator determines that it is a DLT ○ When triggering the termination criteria defined in the protocol If it causes an interruption in the administration schedule

[0488] Patients experiencing DLT are monitored weekly until toxicity stabilizes, and then every two weeks until normalization. - will be done.

[0489] Dosage escalation and treatment period The procedure will be performed on an outpatient basis. A standard dose-escalation phase I design will be used. Three subjects will be included. This is registered at each dose level without a DLT. For details on dose escalation, please refer to the table below. I want to.

[0490] [Table 39]

[0491] 177 Lu-DOTA 0 -Tyr 3 - The selection of the starting dose of octreotate and antibody is, Results from previous clinical trials of each compound used as a single agent and combinations in clinical trials This is based on the fact that it has not been tested in the trial. 177 Lu-DOTA 0 -Tyr 3 - The first dose of octreotate is administered two weeks after the first dose of the antibody. The study is Intravenous administration of amino acids has been shown to have a renal protective effect

[46] . 1 L of 0.9% NaCl containing 2.5% lysine and 2.5% arginine; 250 mL / hour The interval is, 177 Lu-DOTA 0 -Tyr 3 - 30 minutes before and immediately after administering octreotate. It will start in the next four hours.

[0492] The antibody is administered as a fixed dose of 240 mg via intravenous infusion over 30 minutes every two weeks. Antibodies are administered. Antibodies are given for progressive diseases, patient withdrawal, or toxicity.

[0493] Dose setting 177 Lu-DOTA 0 -Tyr 3 - The following dose levels of octreotate are antibody and These can be searched in combination (Table 2): ●Dose level-1 (starting dose): 3.7 GBq (100 mCi) ●Dose level 0: 7.4 GBq (200 mCi) 177 Lu-DOTA 0 -Tyr 3 - Octreotate is administered in a total of 4 doses every 8 weeks. It is possible.

[0494] [Table 40]

[0495] Patient rotation Three patients within a certain dose level may spontaneously begin to move to the next higher dose level. The patient must be observed for one cycle (56 days) before withdrawal. If a patient drops out of the trial before completing 56 days of therapy without experiencing T, an additional patient will be charged. It can be added to that dose level.

[0496] Phase II The Phase II portion is 177 Lu-DOTA 0 -Tyr 3 - Octreotate and antibodies At the start of the combination therapy, there is no disease progression (response cases and stable disease), and the treatment is platinum-based. Standard first-line chemotherapy (e.g., platinum and etoposide or irinotecan for 4-6 months) The patients will consist of those with ES-SCLC who have completed the CR (Clinical Cycle). Next, eligible patients will be: Two arms are randomly assigned: one is, 177 Lu-DOTA 0 -Tyr 3 - The other arm was treated with a combination of octreotate and antibody, and the other arm was treated with a standard Follow-up (observation) continues after the completion of chemotherapy. Radiation therapy is administered after chemotherapy. For patients who have not undergone the procedure, randomization must be performed within 6 weeks of the last chemotherapy cycle. The experimental treatment must be initiated within two weeks of randomization. After the therapy, radiation therapy (including prophylactic cranial and / or thoracic radiation) is administered. For patients, randomization occurs within 9 weeks of the last chemotherapy cycle, but radiation therapy It must be done at least two weeks after the law is completed. 177 Lu-DOTA 0 -Ty r 3- The first dose of octreotate cannot be administered within 8 weeks of radiotherapy. . ● For all patients who have signed the Informed Consent Form (ICF), Leaning numbers are assigned in chronological order, starting with the smallest number available on site. It can be done. ● Each patient has a unique patient identification number consisting of a facility number (4 digits) and a screening number (3 digits). They are identified by a different number (Patient ID No.). ● The e-CRF assigns a unique randomization number to each patient, which is used to assign patients to the treatment arm. It is used to connect things. ● Randomization is based on the NETSPOT® PET tumor uptake score (grades 2, 3, and The data is stratified according to (b) 4).

[0497] The process is defined as a 56-day administration. Antibodies are used to treat progressive disease, patient withdrawal, or toxicity. It is given by: For patients randomized to the observation group, the crossover at disease progression is: Since the primary endpoint is PFS (progression-free survival) and not OS (overall survival), this is acceptable.

[0498] Test Procedure Screening / Baseline Procedure Those who meet all eligibility criteria will be registered for the exam. Eligibility for this exam will be determined. The evaluation, which is conducted exclusively for this purpose, is carried out after informed consent has been obtained. The evaluations conducted for clinical indication (which do not exclusively determine eligibility for the trial) Even if the test was conducted before informed consent was obtained, the baseline value It may be used for the following purposes. All screening procedures use the test drug unless otherwise specified. It must be carried out within four weeks prior to the start of the program. The screening procedure includes the following: nothing. ●Complete medical history and vital signs, physical examination including height, weight and ECOG performance score Inspection. ●Baseline imaging: Patients undergo computed tomography (CT) of the chest, abdomen, and pelvis. Baseline examination based on scan, brain MRI or CT, and FDG-PET (from the base of the skull to the mid-femur). Line radiograph evaluation should be performed. Two NETSPOT(registered trademark) PET scans should be performed. A scan is performed, the first of which should be within 4 weeks before the start of chemotherapy (preferably) or during chemotherapy This is immediately after the start of the procedure. This scan is used to check SSTR2 expression and the patient's response to this test. Evaluate the applicant's eligibility. A second NETSPOT® PET scan is possible. Ideally, this should be performed from the end of chemotherapy (ideally within one week before the start of the test procedure). This scan is for exploratory analysis of the final modification of SSTR2 expression by chemotherapy. It is used for the following purposes: The patient is present after the completion of chemotherapy, and the patient is present before or during chemotherapy. If you do not have the NETSPOT® PET scan to be performed, NETSPOT T(registered trademark) PET scans are taken to determine patient eligibility. External images Image examination is permitted at the discretion of the PI. ● Electrocardiogram (EKG) ● Clinical tests (unless otherwise specified, baseline obtained within one week prior to the start of treatment) test) ○ Hematological profile: Complete blood count (CBC) with white blood cell percentage and platelet count, profile Thrombin time / International Normalized Ratio (PT / INR), Activated Partial Thromboplastin Time (a PTT). Biochemical profile: Sodium, potassium, calcium, phosphorus, magnesium, Blood urea nitrogen (BUN), creatinine, glucose, aspartate aminotransfer Alkaline phosphate enzyme (AST), alanine aminotransferase (ALT), alkaline phosphine Tase, lactate dehydrogenase (LDH), bilirubin, albumin. ○ Calculation of baseline glomerular filtration rate (GFR). ○ Serum or urine samples from women of childbearing age within 24 hours prior to the start of the study drug administration. Ta-hCG. ○ Viral markers: HBsAg, anti-HCV, and anti-HIV levels within 3 months prior to the start of treatment. ○ Amylase, lipase, thyroid function tests (TSH, free T3, free T4).

[0499] Procedure during treatment Patients undergoing the trial procedure will be followed up every two weeks and will receive the following treatments (unless otherwise instructed). (Unless otherwise.) ●Medical history and physical examination. ●Clinical tests: Hematological profile (CBC with white blood cell percentage). Biochemical profile Ru. ● Thyroid function tests are performed approximately every four weeks on subjects who have received the antibody test. ● Tumor imaging is performed every 8 weeks (within one week of starting the next cycle). ●NETSPOT (indicating a metabolic response) on day 1 (±3 days) of cycle 2. (Registered Trademark) PET scan. ● 177 Lu-DOTA 0 -Tyr 3 - Pregnancy within 24 hours prior to administration of octreotate Serum or urine beta-hCG in female patients of reproductive age.

[0500] Patients randomized for observation will be followed up every four weeks, and the following will be performed: ●Medical history and physical examination. ● Clinical tests: Hematological and biochemical profiles. Tumor imaging is performed every 8 weeks.

[0501] Thirty days after the completion of the procedure, if the patient is available, the following will be obtained: ●Medical history and physical examination. ●Clinical tests: Hematological and biochemical profiles. Thyroid function tests.

[0502] Reference All publications, patents, and accession numbers referred to herein are the same as those of each individual publication or This specification indicates that the patent is invoked by reference in a specific and individual manner. The whole is referenced by this.

[0503] Equal portions Specific embodiments of the present invention have been discussed, but the foregoing specification is illustrative. This is not limited to the above. Those skilled in the art will find this specification and the following claims useful. Many variations of the present invention will become apparent. The full scope of the present invention is its equivalents. By referring to the claims in their entirety and this specification in conjunction with such variations, It must be decided.

Claims

1. Peptide for use when treating somatostatin receptor overexpressing cancers in the target population. It contains a receptor radionuclide therapy (PRRT) agent and one or two cancer immunotherapy (I-O) agents. The combination is such that the I-O therapeutic agent is a LAG-3 inhibitor, a TIM-3 inhibitor, G ITR agonists, TGF-β inhibitors, IL-15 / IL-15RA complexes, and PD-1 inhibitors Selected from the group consisting of harmful agents, the PD-1 inhibitors include spartalizumab and pembrolizumab. Mab, pidilizumab, durvalomab, atezolizumab, avelumab, MEDI068 0, REGN2810, TSR-042, PF-06801591, BGB-A317, Selected from the group consisting of BGB-108, INCSHR1210, and AMP-224, combination.

2. A method for treating somatostatin receptor overexpressing cancer in a subject, wherein the peptide receptor A combination of radioactive radionuclide therapy (PRRT) agents and one or two cancer immunotherapy (I-O) agents. The procedure includes administering the I-O therapeutic agent to the subject, wherein the I-O therapeutic agent is a LAG-3 inhibitor, TIM- 3 inhibitors, GITR agonists, TGF-β inhibitors, IL-15 / IL-15RA complex and A PD-1 inhibitor is selected from the group consisting of spartalizumab, Pembrolizumab, pidilizumab, durvalomab, atezolizumab, avelumab, M EDI0680, REGN2810, TSR-042, PF-06801591, BGB - From the group consisting of A317, BGB-108, INCSHR1210 and AMP-224 The method to be chosen.

3. The aforementioned PRRT agent is the radionuclide lutetium-177 ( １７７ Lu) and chelating agents A combination for use according to claim 1, comprising a bound somatostatin receptor-binding molecule The method according to claim 2.

4. The somatostatin receptor binding molecules mentioned above include octreotide, octreotate, and lanreotide. A selection from the group consisting of tide, bapleotide, pasireotide, and satreotide, claim The combination or method for use described in 3.

5. The chelating agent is 1,4,7,10-tetraazacyclododecane-1,4,7,10 - A combination or method for use according to claim 4, wherein the compound is tetraacetic acid (DOTA).

6. The somatostatin receptor-binding molecule linked to the chelating agent is DOTA-OC: [DOTA0, D-Phe1] Octreotide, DOTA-TOC: [DOTA ０ , D- Phe １ , Tyr ３ ] Octreotide (i.e., edtreotide), DOTA-NOC: [D OTA ０ , D-Phe １ , 1-Na ３ ] Octreotide, DOTA-TATE: [DO TA ０ , D-Phe １ , Tyr ３ octreotate (i.e., oxodotreotide), DO TA-LAN: [DOTA] ０ ,D-β-Nal １ ]ランレオチド、DOTA-VAP:[ DOTA ０ , D-Phe １ , Tyr ３ ] bapreotide, satreotide, trizoxetane and Selected from the group consisting of tetraxetane and threotide for use as described in claim 3 A combination or method.

7. The aforementioned PRRT agent is lutetium ( １７７ Lu) Oxodotreotide (that is １７７ Lu[ DOTA ０ , D-Phe １ , Tyr ３ The use of octreotate as described in claim 1. A combination for use or the method according to claim 2.

8. The aforementioned PRRT agent is (a) A complex, (ai) Radioactive nuclide 177Lu (lutetium-177), which is 250 to 500 Radionuclide 177Lu(Lu) at concentrations that provide radioactivity by volume measurement in MBq / mL Tethium-177), and (aii) DOTA-linked somatostatin receptor-binding peptide The complex formed by; (b) Stabilizer against radiolysis, (bi) Gentisic acid at a concentration of 0.5 to 1 mg / mL , and (biii) ascorbic acid at a concentration of 2.0–5.0 mg / mL; (c) Diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg / mL or its salt; and (d) Acetate buffer, (di) Acetic acid at a concentration of 0.3 to 0.7 mg / mL; and (dii) Sodium acetate at a concentration of 0.4–0.9 mg / mL It is composed of a pH of 4.5 to 6.0, preferably 5.0 to 5.

5. The acetate buffer to be provided Formulated as a pharmaceutical aqueous solution containing the above, for use as described in any one of claims 3 to 7 A combination or method.

9. Gentisic acid is present in the complex formation of components (ai) and (aii), and ascorbic acid The acid is added after the complex formation of components (ai) and (aii), as described in claim 8. A combination or method for this purpose.

10. The LAG-3 inhibitor is LAG525, BMS-986016, or TSR-033. A combination for use as described in any one of claims 1, 3 to 9, or The method described in any one of the requests 2 to 9.

11. The TIM-3 inhibitor is MBG453 or TSR-022, claims 1, 3 to 1 A combination for use as described in any one of claims 0 or any one of claims 2 to 10 Method of description.

12. The aforementioned GITR agonists are GWN323, BMS-986156, MK-4166, MK-1248, TRX518, INCAGN1876, AMG 228 or INBRX A combination for use according to any one of claims 1, 3 to 11, selected from -110. A combination or the method according to any one of claims 2 to 11.

13. The TGF-β inhibitor is XOMA 089 or fresolimmab, claims 1, 3. A combination for use as described in any one of claims 12 or any one of claims 2 to 12. The method described in section [section number].

14. The IL-15 / IL-15RA complex is NIZ985, ATL-803, or CYP A combination for use according to any one of claims 1, 3 to 13, selected from 0150. A combination or the method according to any one of claims 2 to 13.

15. Use according to any one of claims 1, 3 to 14, comprising one or two further anticancer agents A combination for or the method according to any one of claims 2 to 14.

16. The aforementioned further anticancer agents include octreotide, lanreotide, baproreotide, and pasireotide. Satreotide, everolimus, temozolomide, telototristat, sunitinib, sulfur Selected from the group consisting of atinib, ribociclib, entinostat, and pazopanib. The combination or method for use described in claim 15.

17. The somatostatin receptor overexpressing cancer is a neuroendocrine tumor (NET), claim 1. , a combination for use as described in any one of claims 3 to 16 or any one of claims 2 to 13 The method described in item 1.

18. The aforementioned neuroendocrine tumors (NETs) include gastrointestinal and pancreatic neuroendocrine tumors, carcinoid tumors, and brown oocytes. Cystoma, paraganglioma, medullary thyroid carcinoma, pulmonary neuroendocrine neoplasm, thymic neuroendocrine neoplasm, carcinoma Idiopathic tumor or pancreatic neuroendocrine tumor, pituitary adenoma, adrenal tumor, Merkel cell carcinoma, breast cancer, non-homopathetic Dikin lymphoma, Hodgkin lymphoma, head and neck tumors, urothelial carcinoma (bladder), renal cell carcinoma, liver cell carcinoma Celluloid carcinoma, GIST, neuroblastoma, cholangiocarcinoma, cervical tumor, Ewing's sarcoma, osteosarcoma, small Cellular lung cancer (SCLC), prostate cancer, melanoma, meningioma, glioma, medulloblastoma, hemangioblastoma, ten A selection from the group consisting of primitive neuroblastoma, neuroectodermal tumor, and sensory neuroblastoma, as per claim 17. The combination or method of use described.

19. The aforementioned neuroendocrine tumors (NETs) include functional carcinoid tumors, insulinomas, and gust tumors. Phosphate-producing tumors, vasoactive intestinal peptide (VIP) tumors, glucagon-producing tumors, serotonin A group consisting of histaminomas, ACTH tumors, pheochromocytomas, and somatostatin-producing tumors. A combination or method for use according to claim 17, selected from the above.

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